TW200410687A - Novel compounds - Google Patents

Abstract

The present invention relates to new compounds of formula (I), wherein R1, R2, R3, R4, R5 and A are defined as in formula (I), a process for their preparation and new intermediate prepared therein, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy, especially in the treatment of c-Jun N-terminal kinase (JNK) mediated conditions in mammals, particularly Alzheimer's Disease.

Description

0) 0) 200410687 玖, sounding 啰 τ _ (the description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments and the drawings simply explain the technical field The present invention is related to formula U) novel compounds It can be in the form of a free base, a salt of a 'dropping compound' or a solvate of a salt, a medical compound containing the compound, and its use in therapy. The invention further relates to a process for the preparation of compounds of formula (I) and to novel intermediates used in the preparation thereof. Prior art Cells can respond to and regulate their environment. Cell surface receptors are one of the most important ways in which Putian cells receive data from external cells. These receptors can transmit data into cells, where they can be transmitted through activation or suppression of repeated biochemical pathways. Protein kinases and phosphatases are important components of the intracellular communication pathway because they allow data to be cascaded to many effector molecules and to amplify signals. Often complex pathway arrangements can activate specific receptors, resulting in a coordinated cellular response. The analysis of these pathways under both normal and diseased conditions has received considerable attention, and pathological perceptions of many disease conditions have been accepted for intracellular communication with abnormal or organic disorders. The MAP kinase signaling pathway can be activated by the involvement of many cell surface receptors. One of these pathways, the JNK pathway (named after one of the critical enzymes in the pathway, named c-jun N-terminal kinase or JNK) is particularly activated by stress or pro-inflammatory cytokines. Activators include LPS, cytokinin tumor necrosis factor (TNFa) and interleukin-1 (IL1), osmotic shock, chemical stress and UV irradiation (Cohen, P. Trends in Cell Biol. 7: 353-361, 1997 ). The target of the JNK path includes many transcription factors, such as c-jun and ATF-2, but not only (Whitmarsh, Α 200410687

(2) and Davis, RVJ.tMο 1. Med. 74: 589-607 1998). These green-turning factors bind to AP-1 and AP-1-like positions in homodimers and heterodimers on the promoters of many genes, resulting in new gene expression (Karin, M. et al., Cur r Op in, Cell. Biol. 9: 240-246 1997). The positive effects on gene expression are not always the result of JNK activation. In T cells, NFATcl's calcineurin-targeted functional site contains a site of JNK activity, which can block the nuclear accumulation of transcription factors. (Ch0W5 C. et al., Mel. Cell. Biol, 20: 5227-5234 2000). Two different genes; JNK1, JNK2 and JNK3, which encode the JNK # prime family. In addition, the splicing patterns of these genes can generate 10 different isoforms; JNK (4, JNK2, 4 and JNK3. (Gupta, S. et al., EMBO J. 1 5: 2760-2770 , 1 996). JNK1 and JNK2 are generally expressed in human tissues, while JNK3 is selectively expressed in brain, heart, and testes (Dong, C. et al., Science 270: 1-4, 1998). JNK1 kinase activity It can increase due to the phosphorylation of two critical residues in the enzyme activation loop, namely Thr 183 and Tyi * 185. Complete activation depends on the phosphorylation of the two residues, although in: Decreased viability of any residue by phosphating (Fleming Y. et al Biochem. J. 352: 1451-54, 2000). The Thr-Pro-Tyr activation motif is the same in all JNK They are retentive in form and are homologous to the Thr-X-Tyr motif (this kinase is p38) seen in the associated MAP kinase activation loop, and the Thr-Y-Ty r in Erk 1 and Erk 2. In the case of p 38, the phosphorylation of the activation ring can cause a change in the configuration of the protein, thus exposing the ATP binding pocket. Although this activation method is in JNK Has not been proven, but a similar method is believed to be 200410687

occur. .. _ So far, only two related enzymes, MKK4 and MKK7, are known to phosphorylate JNK. MKK4 (also known as JNKK1) can differentially phosphorylate Tyr 185, although it can also phosphorylate Thr 183. (Lawler, S. et al., Current Biology 8: 1387-1390, 1998). MKK4 can also phosphorylate p3 8 in test tubes, but it is uncertain whether it can occur in vivo (References). In contrast, MKK7 (also known as JNKK2) can only be phosphorylated butanium 1 ^ 183 (1 ^ Zhu 41 *, 8. et al., Current Biology 8: 1 3 87-1 3 90 1 998). No other target of MKK7 has been found, and it appears to be a JNK-specific activator. There are reports that many MAPKK4 can activate JNK, and this is caused by the activation of either MKK4 or MKK7, including MEKK1, MEKK2, TAK1 , MCK. The selectivity of JNK messaging is mostly achieved through the specific interaction of the messaging components, and the use of backbone proteins can facilitate it. One of such backbone proteins, JNK interaction protein (JIP-1), can selectively bind JNK1, MKK7 and MLK (Yasuda, J. et al ·, Mol · Cell · Biol, 19: 7245-7254, 1999 ) ° JNKK's 1, 2 :, and 3 have been selectively eliminated in mice, and can be performed singly and in combination through the introduction of foreign gene expression through two negative patterns of gene deletion and / or kinase advantage. (Dong, C. et al ·, Science 282: 2092-2095 1 998; Yang, D. et al.? Immunity 9: 5 75 -5 85, 1 998; Dong, C ·, et al ·, Nature 405: 9 1-94 2000; Yang, D. et al., Nature 389: 865-870 1997). Disrupted mice with the JNK 3 gene target can develop normally and protect them from the expected death of neurons slaughtered by the stimulus toxin. This finding suggests that a specific inhibitor of JNK 3 200410687

It can be effectively used for the treatment of neurological disorders characterized by cell death, such as Alzheimer's disease and stroke. Disrupted mice on JNK 1 or 2 can also develop normally. Peripheral T cells' taken from either type of mouse can be activated to make IL2, but in these two cases, there is still a lack of T h 1 cell development. In the case of JNK // mouse, this is due to the inability to produce r interferon (this interferon is a critical cytokine necessary for Th 1 cell differentiation). In contrast, JNK2-/-mice produce r-interferon, but cannot respond to cytokines. Similar deletions can be observed in T cells in which the MKK7 gene has been disrupted (normal production of IL2 but blocked in Th1 cell differentiation), confirming the role of the JNK pathway in T cell differentiation (Dong, C ·, et al ·, Nature 405: 91-94 2000). MKK4-1 · mice have a more significant lack of T cell activation and are blocked in IL2 production (Nishina, H. et al., J. Exp. Med. 186: 941-953, 1997). However, based on the phenotype seen in JNK-/-mice, this can be caused by the collapse of other MKK4 characters. Rats that collapsed in both JNK 1 and JNK 2 will die in the womb, showing the important role of JNK enzymes in development. However, T cells from double knockout mice are very similar to T cells without μ K K 7. These data confirm the important role of the J N K pathway in T cell biology. The activation of the JNK pathway has been demonstrated in many disease localizations, and it can be deduced that specific inhibition of JNK activity can provide effective treatment. As described above, strong evidence of JNK role in neurological diseases can be obtained from JNK 3 deficient mice. Synovial fibroblasts isolated from the joints of rheumatoid patients with rheumatoid arthritis can activate JNK in situ and can produce MMP's without any additional stimuli. It can also act on inflammatory stimuli such as tnf Or IL1 strong 200410687

(5) Reactions to further increase the performance of M MP (H a η · Z · e 11 a 1 ·, J Pharmacol Exp. Ther. 29 1: 1 24- 1 3 0 1 9 9 9; Okamoto, K. e t. al. Arth. & Rheum. 40: 9 1 9-926 1 997). MMP performance can also be blocked by inhibitors of JNK enzyme activity. This same inhibitor can also block joint disintegration in TF experimental mice (H an. Z. Eta 1., J. Clin · Invest · 1 0 8:73-8 1,200 1), so Strong support is provided for the usefulness of selective compounds of formula (I) in human diseases. It appears that this protective effect is due to the hindered expression of the MMP gene, since many MMP genes are under the control of the AP-1 element in its upstream promoter region. Indeed, it has been shown that the defamatory performance of MMP3, 9 and I3 can be regulated by activation of JNK and AP-1 (Gum, R. et. Al., Oncogene, 14: 1481-1493, 1997). JNK plays an important role in cell zeroing (Davis RJ. Cell. 1 0 3 ·· 2 3 9-2 5 2 2 0 0 0). For example, U.V. JNK is necessary for declining cell death through the cytochrome C-mediated pathway. (Tournier, C. et al., Science 2 8: 8 7 0-8 7 4, 2 0 0 0). Hemostasis, hemorrhage plus reperfusion, and the blood flow itself have been shown to be accompanied by activation of JNK. The transposition of JNK's dominant angular pattern into cells can avoid cell death, which may explain the potential use value of JNK in the withering of cells characterized by stress. JNK pathway has been observed in many human tumors and transformed cell lines

Pathway activation (Davis RJ. Cell. 103: 239-252, 2000). Indeed, one of JNK's main targets, c_jUI1, was originally identified as an oncogene, showing the potential of this pathway to participate in unregulated cell growth. JNK can also regulate the phosphorylation of p 5 3 and thus the progression of the cell cycle (Chen T. et al., Mol. Carcinogenesis 15: 215-226 1 996). -10- 200410687

Therefore, the inhibitory effect of J N K is beneficial in some human cancers. Based on current knowledge of JNK communication, especially JNK 3, it is known to be involved in the field of neurodegenerative diseases driven by cell death, such as: Alzheimer's disease, Parkinson's disease, ALS, mochi and Seizures, Huntington's disease, traumatic brain injury, and hemorrhagic and hemorrhagic * strokes. Therefore, there is a high medical need for JNK-specific inhibitors that can treat various conditions related to JNK activation. Description of the invention The object of the present invention is to propose compounds that have an inhibitory effect on JNK and have good bioavailability. The invention proposes compounds of formula (I)

among them:

Ri is hydrogen, CHCHR6, CCR6, C02R7, NHC0R7, CN or halogen; R2 is hydrogen, halogen, CN, OCu alkyl, or 5- or 6-membered heterocyclic ring, containing 1, 2 or 3 independently selected from N; Heteroatoms of 0 and S; R3 is hydrogen or halogen; R4 is hydrogen, OH, NH2, N02 or NHR8; R5 is hydrogen, COR9, CHO, CH2OR10, oh, OCu alkyl, NH2, NRWR1 1, NHCONR10Rn, NHCOR10, c〇NR12R13, CONHR7 -11-200410687

, R7, or R4 and R5 plus the carbon atom to which they are attached form a 5-, 6-, or 7-membered pyrimidine ring; R6 is Ci_6 alkyl, and 1, 2 or 3 are independently selected from hydroxyl, OCu alkane Substituted with OCu alkyl OH and NR12R13 substituents; R7 is CONHOCu alkyl OH, or Cb6 alkyl optionally 1, 2, 3 or 4 substituted independently selected from hydroxy, OCu alkyl, and NR12R13 R7 is substituted by phenyl, or R7 is phenyl or 5-or 6-membered heterocyclic ring, and contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; R8 is COR14 or (CH2) nQ, where η is 1, 2 or 3, and Q is NR15R16 or 5-, 6- or 7-membered saturated heterocyclic ring, which contains 1, 2 or 3 heteroatoms independently selected from N, 0 and S, at least one of which is N, except that when Q is a heterocyclic ring not linked by N, η may only be 1; R9 is a hydroxyl group or an OCl_6 alkyl group, which may be substituted by a 5- or 6-membered heterocyclic ring, and this heterocyclic ring contains 1 , 2 or 3 heteroatoms independently selected from N, 0 and S; R10 and R 1 1 are independently selected from hydrogen and Ci-6 alkyl, and this alkyl is optionally selected from 1, 2 or 3 independently Light group, substituted by OCu alkyl and NR12R13 substituents; R12 and R13 are independently selected from hydrogen and Cu alkyl Or R12 and R13 together form a 5- or 6-membered heterocyclic ring, this heterocyclic ring contains 1, 2 or 3 heteroatoms independently selected from N, 0 and S, and the ring may be selected from more than one independently selected Substituted by a substituent of a keto group, a keto group, a Ch6 alkyl group, a 0-6 alkyl group, and a Cb6 alkyl group OH; R14 is hydrogen or a Cb6 alkyl group; R15 and R16 are independently selected from hydrogen and Ci-6 alkyl group; A Is 5- or 6-membered saturated, or 5- or 6-membered aromatic ring, containing a -12-200410687 as required

More than two independent ii heteroatoms of N, 0 and S, which contain more than one — C = 0 group, and the ring may be one or more independently selected from Cu alkyl 'S02C 1_6 alkyl, SOCi: 6 as required The alkyl group, C02H and CHO are substituted by a substituent, and may be in the form of a solvate of a base, a salt, a solvate or a salt thereof. One aspect of the present invention relates to compounds of formula (I), wherein: R2 is hydrogen, halogen, CN, or a 5- or 6-membered heterocyclic ring, which contains 1, 2 or 3 heterocycles independently selected from N, O and S Atom; R5 is hydrogen, COR9, CHO, CH2OR1G, OH, OCl.6 alkyl, NH2, NR10RU, NHCONRMR11, NHCOR10 or R4 and R5 plus the carbon atom attached to it can form 5-, 6-or 7-member Lactamamine ring; R6 is Ci-6 alkyl, substituted by 1, 2 or 3 substituents independently selected from hydroxyl, OCi-6 alkyl and NR12R13; R9 is hydroxyl or OCu alkyl; and R12 and R13 are independently selected from hydrogen and Cb6 alkyl. In another aspect of the invention, R1 is hydrogen, CN, CO2CH3, CO2CH2CH3, CO2CH2CH20H, halogen or NHCOR7, wherein R7 is furyl or phenyl. In a further aspect of the invention, R2 is hydrogen or chlorine. In yet another aspect of the invention, R3 is hydrogen. In yet another aspect of the invention, R4 is hydrogen, NH2, N02 or NHR8, wherein R5 is CH2-pyrrolidine. In yet another aspect of the invention, R4 is NHR8, wherein R8 is CH2-piperidine. In yet another aspect of the invention, R5 is hydrogen or COR9, wherein R9 is hydroxyl. -13-200410687

(9) In another aspect of the invention, R5 is CONR12R13, CONHR7 or R7. -In one aspect of the present invention, R7 is a Cu alkyl group, optionally substituted with 1, 2 or 3 substituents independently selected from a hydroxyl group, an OCu alkyl group and NR12R13, a C1-6 alkyl group of WN-, or R7 Is a phenyl or 5-or 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. In a further aspect of the invention, R7 is CONHOCu alkyl OH, or Cu alkyl is optionally substituted by hydroxy, or R7 is phenyl or a 5- or 6-membered heterocyclic ring containing 1, 2, 3 or 4 independent A heteroatom selected from N and O. In a further aspect of the invention, R7 includes CH2CH2OH, CH2OH and CH (CH2OH) CH2OH. In yet another aspect of the invention, R7 is furyl, piperidinyl, phenyl or CH2CH2OH. Examples of suitable 5- or 6-membered heterocyclic rings include tetrazolyl, pyrenyl, furyl or 17-yl. In yet another aspect of the present invention, A is a 5- or 6-membered saturated or 5- or 6-membered aromatic ring, and if necessary, contains more than one heteroatom independently selected from N, 0 and S; and contains one The above C = 0 group. In one aspect of the invention, the group A plus a phenyl group attached thereto forms a bicyclic group, including the following groups: 200410687

Wherein R4 and R5 are as defined in formula (I). One aspect of the present invention relates to compounds of formula (I), in which the group A, coupled with the lacking phenyl group, forms a bicyclic group of formula (A) or (B):

Wherein R4 and R5 are as defined in formula (I). Another aspect of the present invention relates to the following compounds ^ 8- (1H-benzimidazol-2-ylsulfanyl) -4 (1 H) -quinone, -15- 200410687 (η) 8-[(5- Chloro-1H-benzimidazol-2-yl) sulfanyl] -4 (1 Η) -quinone, 2- (4-keto-1,4-dihydro-quinolin-8-ylsulfanyl Methyl) -1 fluorene-benzimidazole-4-carboxylic acid methyl ester, 8-[(5-chloro-1fluorene-benzimidazol-2-yl) sulfanyl] -5-nitro-fluorene (1fluorene)- Quinidine 5-amino-8-[(5-chloro-1H-benzimidazol-2-yl) sulfanyl] -4- (1Η) -quinone 8-[(5-chloro-1H-benzene Benzimidazol-2-yl) sulfanyl] -5-{[((2r) -pyrrolidinylmethyl] amino}}-4 (1 Η) -quinolones 8-[(5-chloro-1Η-benzene And imidazol-2-yl) sulfanyl] -5-[(4-piperidinylmethyl) amino] -4 (1 hydrazone) -quinolones 5-chloro-2-[(4-keto- 1, rendihydrofluorin-8-yl) sulfur] -1fluorene-benzimidazole- 4-nitrile, 5-chloro-2-[(4-keto-1,4-dihydroquinolin-8-yl ) Sulfur] -1 hydrazone-benzimidazole-4 -carboxylic acid methyl ester N- {5-chloro-2-[(4-keto-1,4-dihydrofluorinoline-8-yl) sulfur] -1Η · Benzimidazole-4-yl} SSSS amine, N- {5-Chloro-2-[[4-keto-1,4-dihydroquinolin-8-yl) sulfur] -1H-benzimidazole -4 -yl}-2 -crotylamine, 4-[(5 -Chloro-1Η-benzimidazole-2-yl) sulfur] -1,3-dihydro-2Η-benzimidazole-2 -pyridine, 7-[(5 -chloro-1Η-benzimidazole-2- ) Sulfur] -2 -keto-2,3 -dihydro-1fluorene-benzimidazole-5 -chinoic acid, 7-[(5-chloro-4- (methoxycarbonyl) -1fluorene-benzimidazole -2 -yl) sulfur] -2 -keto-16-200410687

(12) -2,3-dihydro-1H] benzimidazole-5-carboxylic acid, 7-[(5-chloro-4-[(2-hydroxyethoxy) carbonyl] -1H-benzimidazole- 2-yl) thio] -2-keto-2,3 · dihydro-1 hydrazone · benzimidazole-5 -carboxylic acid, 7-[(5 -chloro-1Η_benzimidazole-2-yl) sulfur ] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5 -carboxylic acid methyl ester, 7-[(5 -Ga-1fluorene-benzimidazole-2-yl) sulfur] -2 · Keto-2,3-dihydro-1fluorene-benzimidazole-5 -carboxylic acid ethyl ester, 7-[(5-chloro-1fluorene-benzimidazol-2-yl) thio] -2-keto-2 , 3-dihydro-1fluorene-benzimidazole-5 · 2-acid 2-morpholin 4-ylethyl, 7-[(5-chloro-6-fluoro-111-benzimidazol-2-yl ) Thio] -2-keto-2,3-dihydro-1 fluorene-benzimidazole-5 -carboxylic acid, 7-[(5-methoxy-111-benzimidazol-2-yl) sulfur] -2-keto-2,3-dihydro-1 fluorene-benzimidazole-5 -carboxylic acid, 7-[(5 -bromo-1 fluorene-benzimidazole-2 -yl) sulfur] -2 -one -2,3 -dihydro-1 hydrazone -benzimidazole-5 -carboxylic acid, 7-[(4-bromo-6 -fluoro-1 fluorene -benzimidazole-2 -yl) sulfur] -2- Keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxylic acid, 7-[(5-chloro-1fluorene-benzimidazole-2-yl) sulfur] -N- [2- (4- Morpholine-4 -ylethyl) -2-keto-2,3-dihydro-1H -Benzimidazole-5-carboxamide, 7-[(5-chloro-1H-benzimidazol-2-yl) thio] -N- [3-dimethylamino] ethyl] -2-one -2,3-dihydro-1H-benzimidazole-5-carboxamide, 4-[(5-chloro-1H-benzimidazol-2-yl) sulfur] -6- [(4-methylpiperazine Phen-1-yl) carbonyl-1,3-dihydro-2H-benzimidazole_2_one, 7-[(5-chloro-1H-benzimidazol-2-yl) sulfur] -N · methyl -2-keto- 2,3-dihydro-17- 200410687

(13) • 1 fluorene-benzimidazole-5 -carboxamide, 7-[(5-chloro-1fluorene-benzimidazol-2-yl) sulfur] -N- (2-hydroxyethyl) -2- Keto-2,3-dihydro-1 fluorene-benzimidazole-5 -carboxamidine, 4-[(5-chloro-1fluorene-benzimidazole-2-yl) sulfur] -6- (pigon 1-ylcarbonyl) -1,3-dihydro-2 fluorene-benzimidazole-2 -one dihydrochloride, 7-[(5-chloro-1fluorene-benzimidazole-2 -yl) sulfur] -2 -Keto-2,3 · dihydro-1fluorene-benzimidazole-5

7-[(5-Chloro-1Η-benzimidazole-2_yl) sulfur] · N · [2- (2-hydroxyethoxy) ethyl] -2 -keto-2,3-dihydro- 1 pyrene-benzimidazole-5 -carboxamide, 4-[(5-chloro-1 pyrene-benzimidazole-2 -yl) sulfur] -6-{[4-(2-hydroxyethyl) piperin -1 -yl] carbonyl} -1,3-dihydro-2 fluorene-benzimidazole-2 -one, 7-[(5-chloro-1fluorene-benzimidazole-2 -yl) sulfur] -2 -one -N-4-piperidine-4 -yl-2,3-dihydro-1 fluorene-benzimidazole-5 -carboxamidinium dihydrochloride, Ν- (3-aminopropyl) -7 · [(5-Chloro-1Η-benzimidazol-2-yl) thio] -2-keto-2,3-dihydro-1-1-benzimidazole-5 -carboxamidinium dihydrochloride,

7-[(5 -Chloro-1Η-benzimidazole-2 -yl)] thio-2 -keto-N-[3-(2 -ketopyrrolidin-1 -yl) propyl] -2, 3 -dihydro-1 hydrazone-benzimidazole-5 -carboxamide, and 4-[(5-chloro-1hydrazine · benzimidazole-2 -yl) thio] -6- (hydroxymethyl) -1, 3-Dihydro-2 hydrazone-benzimidazole-2 -one, in the form of a solvate of a base, a salt, a solvate or a salt thereof. The present invention further proposes a compound of formula (I): -18- 200410687 R4

Among them: R1 is hydrogen, C02R7, NHCOR7, or halogen; R2 is hydrogen or; R3 is hydrogen or halogen; R4 is hydrogen, NH2 or N02; R5 is hydrogen; R7 is Ci_6 alkyl, as required, 1, 2, 3 or 4 substituted by a substituent independently selected from a hydroxyl group; A is a 5-membered aromatic ring containing one or more heteroatoms independently selected from N and 0; and the ring may be, if necessary, more than one independently selected from an alkyl group , S02Ci_6 alkyl, SOCu alkyl and CHO are substituted with substituents, and are shown as salts, solvates or solvates of their salts. The substituents on A may be the same or different, and may be attached to any suitable carbon or nitrogen atom on ring A. In one aspect of the present invention, the group A 'plus a phenyl group attached thereto can form a bicyclic group, including the following groups:

Where R20 is SOCH3, S02CH3, CH3, C02H4 CHO. -19-200410687

〇5) One aspect of the present invention relates to a bicyclic group (c)

(C) wherein R4 and R5 are as defined in formula (I), and R20 is SOCH3, S02CH3, CH3, C02H or CHO. The present invention is further a related compound, which is 7 · [(5-chloro-1H-benzimidazol-2-yl) sulfur] -3- (methylsulfonyl) -1H-indole-4 -amine '5 -Chloro-2- {[3- (methylsulfonamido) -1H-pyridin-7-yl] sulfur} -1H-benzimidazole-4 -carboxylic acid methyl ester, 5-chloro-2- {[ 3-methyl-4-nitro-1H-Win-7-yl] sulfur} -1H-benzimidazole, 7-[(5-chloro-1H-benzimidazol-2-yl) sulfur] -3 -Methyl-1H-pyridin-4-amine '5-chloro-2-{[3- (methylsulfinylSi) -4-nitro-1H-earthin-7-yl] thio} -1Η- Benzo flavor, 7-[(5 -Chloro-1Η-benzimidazole-2 -yl) sulfur] -3-(methylsulfinamidino) -1 hydrazone · dod 4-amine, 4-amine -7-[(5-chloro-1 fluorenyl-benzimidazole-2yl) sulfur] -1 hydrazone-oxindole-3 -aldehyde, and 7-[(5-chloro-111-benzimidazol-2-yl) ) Sulfur] -3- (methylsulfonyl) -111-41 indole, in the form of test, salt, solvate or solvate of its salt. The present invention · In one aspect is a compound of formula (I), wherein: R1 is hydrogen, CHCHR6, CCR6, C02R7, NHCOR7, CN or halogen; -20- 200410687

R2 is hydrogen, halogen plant CW, or 5- or 6-membered heterocyclic ring, which contains 1, 2 or 3-heteroatoms independently selected from N, 0 and S; R3 is hydrogen or halogen; R4 is hydrogen, OH 'NH2, N02 or NHR8; R5 is hydrogen, COR9, CHO, CH2OR1G, OH, OCu alkyl, NH2, NRMR11, NHCONR10Rn, NHCOR10, or R4 is R5 plus carbon atoms attached to it, forming 5-, 6- Or 7-membered pyrimidine ring; R6 is 0: 1-6 alkyl, substituted by 1, 2 or 3 substituents independently selected from hydroxyl, OCl-6 alkyl and NR12R13; R7 is Ci-6 alkyl, depending on It must be substituted by 1, 2 or 3 substituents independently selected from hydroxy, OCm alkyl and NR1 3; or R7 is phenyl or 5-or 6-membered heterocyclic ring, containing 1, 2 or 3 independently selected Heteroatoms of Ν, Ο and S; R8 is COR14 or (CH2) nQ, where η is 1, 2 or 3, and Q is NR15R16 or 5-, 6- or 7-membered saturated heterocyclic ring, which contains 1, 2 Or 3 heteroatoms independently selected from N, 0 and S, at least one of which must be N, but when Q is a heterocyclic ring not linked through N, η may be only 1; R9 is a hydroxyl group or an OCu alkyl group; R1G and R11 are independently selected from hydrogen and Ci_6 alkyl, which may be 1, if necessary, 2 or 3 independently selected from hydroxy, substituted by OCu alkyl and NR12R13; R12 and R13 are independently selected from hydrogen and Cm alkyl; R14 is hydrogen or Cu alkyl; R15 and R16 are independently selected from hydrogen and Ci_6 alkane -21-200410687 (17) The invention states that the continuation sheet A is a 5- or 6-membered saturated or aromatic ring, which may optionally contain more than one-heteroatom selected from N, O and S, and Further, it may optionally contain more than one C = 0 group, and the ring may optionally be substituted by one or more substituents independently selected from Cu alkyl, SC ^ Cu alkyl, SOCl-6 alkyl, and CHO. In the context of the present invention, unless otherwise indicated, the alkyl group, whether alone or part of another group, may be linear or branched. '' C i_6alkylπ represents a straight or branched saturated aliphatic hydrocarbon having 1 to 6 carbon atoms. Examples of the alkyl group include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, second butyl, third butyl, and straight and branched pentyl and hexyl. In this specification, "CHCH" means alkenyl unless otherwise indicated. π 晞 group π includes straight and branched 晞 groups, but refers to individual alkenyl groups such as 2-butynyl, and specifically refers to only the linear version. Unless otherwise stated, " alkenyl " advantageously refers to a chain having 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. Therefore, "CHCHR6 '' refers to a fluorenyl group substituted with R6. In this specification, unless otherwise indicated," C C '' "refers to a decanyl group. &Apos; ' Alkynyl ' includes both straight and branched alkynyl, but refers to individual alkynyls, such as 2-butynyl specifically refers to the straight-chain version only. Unless otherwise indicated, "alkynyl" advantageously refers to a chain having 2 to 5 carbon atoms, preferably 3 to 4 carbon atoms. Therefore, '' CCR6f4l is R6 substituted alkynyl. The term "'halo'" includes fluorine, chlorine, bromine, and broken groups. " Heterocycle π represents a 3- to 10-membered, aromatic, non-aromatic partially or fully saturated fe group, which contains one or two rings and at least one heteroatom. Examples of this heterocycle include? Beyondyl, p-bihaki, succinyl, p-sedenyl, imidyl, p-type gorge -22- 200410687

(18) radical, Isaki Kisaki ", p τττ seat group, p ratio fluorenyl group, benzocryl group, carboxyl group, -isoindolinyl group, benzimidyl group, tago , Pyridyl, pbicyl, tetrazolyl, succinyl, tonyl, dipyridyl, yttrium, ytyl, morphyl, 4 π-based, 2 No. olizinone or tetrahydrocranyl. Certain compounds of formula (I) may exist in stereoisomeric forms. It should be understood that the present invention includes all geometric and optical isomers of formula (I), and mixtures thereof including apoplastics. The invention relates to any and all tautomeric forms of the compounds of formula (I). The invention relates to the use of compounds of formula (I) (as defined above) and their salts. The salts used in the pharmaceutical composition are pharmaceutically acceptable salts, but other salts can also be used in the production of compounds of formula (I) and pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of the compounds of the present invention are acid addition salts, such as inorganic or organic acids. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention are metal test salts, soil test metal salts or salts formed with organic tests. The invention also relates to compounds of formula (I), wherein the salts are pharmaceutically acceptable salts. Medical use Surprisingly, it has been found that the compounds of the present invention, as a free base, a salt, a solvate or a solvate of a salt thereof, are all suitable for inhibiting JNK. Therefore, the compounds of the present invention are expected to be useful in the treatment of JNK-mediated conditions, i.e., the compounds can produce JNK inhibitory effects in mammals, including humans, in need of this therapy. And "JNK-Mediated Condition '" as used herein means any disease or other harmful condition in which JNK is known to play a role. Such conditions include inflammatory diseases, autoimmune diseases, destructive osteodystrophy, and proliferative disorders -23-200410687

(19) Symptoms, cancer, infectious diseases, neurodegenerative diseases, allergies, reperfusion / hemostasis during stroke, heart invasion, angiogenic disorders, organ hypoxia, angiogenesis, cardiac hypertrophy, and thrombin The platelet agglutination effect and the conditions related to prostaglandin endoperoxidase synthase-2 are not limited thereto. Inflammatory diseases that can be treated or prevented by the compounds of the present invention include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies, and adult respiratory distress syndrome. Autoimmune diseases that can be treated or prevented by the compounds of the present invention include glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grove's disease, autoimmune gastritis, diabetes , Autoimmune hemolytic anemia, Autoimmune neutropenia, Thrombocytopenia, Atopic dermatitis, Chronic active hepatitis, Myasthenia gravis, Multiple sclerosis, Inflammatory bowel disease, Colon ulcer Crohn's disease, psoriasis, and intra-graft host disease, but it is not limited to this. Destructive skeletal disorders that can be treated or prevented by the compounds of the present invention include, but are not limited to, osteoporosis, osteoarthritis, and skeletal disorders associated with multiple myeloma. Proliferative diseases that can be treated or prevented by the compounds of the present invention include acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, and tumor formation mediated by HTLV-1, But it is not limited to this. Angiogenic disorders that can be treated or prevented with the compounds of the present invention include solid tumors, neovascularization of the eye, and infant hemangiomas. Compounds of the invention -24- 200410687

Treated or prevented: Infectious diseases include bulging disease, septic shock, and Shiga-'s disease. Viral diseases that can be treated or prevented by the compounds of the present invention include acute hepatitis infections (including hepatitis A, B, and C), HIV infection, and CMV retinitis. Neurodegenerative diseases that can be treated or prevented by the compounds of the present invention include Alzheimer's disease, Parkinson's disease, amyotrophic lateral ventricular sclerosis (ALS), epilepsy, seizures, Huntington's disease, traumatic brain injury, Hemostasis and hemorrhagic shock, cerebral hemorrhage and neurodegenerative diseases, such as neurodegenerative diseases driven by withering cells, can be caused by trauma, acute hypoxia, hemorrhage or glutamate neurotoxicity. n JN K-mediating conditions π also includes hemorrhage / reperfusion during stroke, heart invasion, myocardial hemorrhage, organ hypoxia, angiogenesis, cardiac hypertrophy, liver hemorrhage, liver disease, congestive heart failure, pathological Immune responses such as those caused by T cell activation and thrombin-induced platelet aggregation. In addition, the compounds of the present invention can inhibit the performance of the defamated inflammatory protein. Therefore, the compounds of the present invention can treat or prevent other 'JNK-mediated conditions' including edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, toothache and arthritis pain. A specific example of the present invention relates to the use of a compound of formula (I), which can be used for treating a compound selected from Alzheimer's disease, Parkinson's disease, ALS, epilepsy and seizures, Huntington's disease, traumatic brain injury , And the status of JNK mediation, one of the components of hemorrhagic and hemorrhagic stroke. In a preferred embodiment of the invention, this condition is Alzheimer's disease. The invention also relates to the use of a compound of formula (I) (as defined above), which may be -25-200410687

Manufactured to treat JNK-mediated conditions and any of the other conditions mentioned above. _ The invention further relates to the use of compounds of formula (I) (as defined above), which can be made into medicines to treat Alzheimer's disease, Parkinson's disease, ALS, mochi and seizures, Huntington 'S disease, traumatic brain injury, or hemorrhagic stroke. The present invention relates to the use of compounds of formula (I) (as defined above) and can be made into pharmaceuticals to treat Alzheimer's disease. According to another specific example, the present invention proposes a method for treating the condition of JNK mediation and any of the aforementioned conditions, which method comprises administering a therapeutically effective dose of a compound of formula (I) to a patient in need of the therapy. In the description of the present invention, "treatment" and "'treatment" also include' 'prevention' unless there is a specific indication to the contrary. And π treatment ", π treatment" and "therapeutic" should be interpreted accordingly. As used in π patient ff, it means an animal, preferably a human. In this specification, unless otherwise indicated, " `` Inhibitor '' means a compound that can partially or completely block the transduction pathway, leading to the production of a ligand reaction. ΠStatus π — The word, unless otherwise indicated, means anything related to JNK activity Disorders and diseases. Non-medical use In addition to its medical use, compounds of formula (I) in free base, salt, solvate or solvate of salt can be used as pharmacological tools to develop and standardize test tubes. And in vivo test system to evaluate the effects of JNK-related activity inhibitors on laboratory animals (such as cats, dogs, rabbits, monkeys, rats, and mice) as part of the research on new therapeutic agents. -26- 200410687

Pharmaceutical composition-The present invention proposes a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above "for application in therapy. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be adjusted into a medical combination The composition can be administered to animals or humans. The composition of the present invention can be administered orally, parenterally, by inhalation spray, topically, anally, nasally, bucally, vaginal or implanted storage tank. '' Such techniques include subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intra-rib, intrathecal, intrahepatic, intra-wound and intracranial injection and infusion techniques. Preferably, the composition is taken orally and administered intraperitoneally or intravenously. The pharmaceutical composition of the present invention can be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, lozenges, aqueous suspensions or solutions. In the case of oral lozenges, commonly used carriers include gluten L sugar and corn starch. Lubricants such as magnesium stearate can also be added. Examples of useful #release agents include lactose and dried corn starch. When suspensions are required, the active ingredients can be combined as emulsifying and suspending agents. If necessary, certain sweeteners, fragrances or colorants can also be added. In general, the above composition can be used in a conventional manner. It is prepared using pharmaceutically acceptable excipients, diluents and / or inert carriers. The dosage of the JN K inhibitor to produce a single dosage form in combination with a carrier substance can vary depending on the host being treated and the particular mode of administration. Preferably, in the blended composition, the inhibitor may be administered at a dose of between 0.01 mg / kg body weight / day. It should be understood that the specific dose and the course of treatment for any particular patient may depend on a variety of factors, including the particular compound applied -27- 200410687

The activity of the patient, the patient's age, weight, general health status, gender, food intake, time of administration, excretion rate, drug coordination, and the judgment of the attending physician and the severity of the disease being treated. Accordingly, the present invention also relates to a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) as an active ingredient, together with pharmaceutically acceptable excipients, diluents and / or inert carriers. This pharmaceutical composition can be used to treat conditions mediated by JNK, and any of the other conditions mentioned above. An example of the pharmaceutical composition of the present invention is an injectable solution containing each compound of the present invention (4-[(5-chloro-1H-benzimid-2-yl) sulfur] -6- (piperazine- 1-ylcarbonyl) -1,3-dihydro-2H-benzimidazol-2-one dihydrochloride), or a pharmaceutically acceptable salt thereof, as defined above, and sterile water, if necessary Add steel hydroxide or hydrochloric acid to bring the pH of the final composition to about pH 5 and add a surfactant as needed to aid dissolution. Liquid composition containing a hydrazone compound of formula (I), or a pharmaceutically acceptable salt thereof, and dissolved in water. _ Liquid composition mg / ml 4-[(5-chloro-1H-benzimidazol-2-yl) sulfur] -6- (piperidinylpyridinyl) -1,3-dihydro-2H-benzo Imidazol-2-one dihydrochloride 5.0% w / v pure water to reach 100% Preparation method The compound of the present invention can be prepared by methods known to similar compound artists, as described in the general scheme below and the following preparation examples. One aspect of the present invention relates to a method for preparing a compound of formula (I) > to (a) and (b) -28- 200410687

Which includes: 0) the compound of formula (II):

> -SH wherein R1, R2 and R3 are as defined in formula (I), or a protected derivative thereof, reacted with a compound of formula (III)

Wherein A, R4 and R5 are as defined in formula (I), or a protected derivative thereof, and L is a leaving group such as halogen, preferably fluorine. This reaction can be carried out in an alcohol, such as n-propanol or ethanol, at 90-100 ° C for 10-48 hours, and the presence of a base, such as 4A hydroxide or #s; Compound of formula (IV):

Where A, R4 and R5 are as defined in formula (I), or protected derivatives thereof; and compounds of formula (V) -29- 200410687 (25) R1

(V)

Wherein R1, R2 and R3 are as defined in formula (I), or a protected derivative thereof, and the plant is a leaving group such as SO2Me or a halogen such as fluorine, chlorine or bromine. This reaction can be carried out in a refluxing alcohol, such as a lower alcohol, such as isopropanol or second butanol, over 2-4 8 hours. According to the following scheme: wherein the nitro group can be reduced with hydrogen in the presence of a catalyst, such as pd or pt / c. The diamine compound is reacted with carbon disulfide in an inert solvent such as dimethylformamide (Org. Synth. 30, 1950, 56) to form an intermediate (II).

The intermediate compound of formula (III) can be prepared by known chemistry according to the following scheme:

-30- 200410687 (26) MO,

NH,

N〇2 S〇2Me

The intermediate compound of formula (IV) can be prepared by known chemistry, for example, according to the following scheme:

The NMe2_e2 7-fluorenyl-benzimidazolone intermediate (IV) can be prepared according to the following procedure, that is, heating the benzimidazolone-5-chinic acid with chlorosulfonic acid (Justus Liebigs Ann. Chem. 1896, (291 ); 328). 7-Chlorofluorenyl can be reduced with a reducing agent, such as triphenylphosphine, to form 7-fluorenyl-benzimidazolone intermediate (IV).

-31-200410687

(27) The intermediate compound of formula (V) 'can be prepared by known chemistry, for example, according to the following scheme: a diamine compound and carbon disulfide are reacted in an inert solvent, such as dimethylformamide (Org. Synth · 30,1 9 5 0, 5 6) to form a '2-mercapto compound. The methylation of the 2- [4-methylated compound can be carried out in a solvent such as acetone or dichloromethane, in the presence of a base such as potassium carbonate, and at room temperature (J. C he m Soc. 1949, 3311-3312, Tetrahedron 1995, 11515-11530). Oxidation of 2-methylsulfanyl group to 2-methanesulfonyl group can be carried out by an oxidant, such as meta-chloroperoxybenzoic acid or oxonium, at room temperature, (J. Chem. Soc., 1 949, 3311- 3312, J. Heterocycl, Chem., 1995, 707-718 "

The skilled artisan understands that in the method of the present invention, certain functional groups in the starting reagent or intermediate compound, such as hydroxyl or amine groups, must be protected with protecting groups. Therefore, the preparation of a compound of formula (I) involves the removal of more than one protecting group at a suitable stage. The protection and deprotection of functional groups are fully described in 'Protective Groups in Organic Chemistry, JWF McOmie, Plenum Press (1973), and' Protective Groups in Organic Synthesis', 2nd edition, TW Greene, & PGM Wuts, Wiley-Intersciences (1991) o Compounds of formula (I) can be converted to further compounds of formula (I) using standard chemistry -32-

V V 200410687 Alkylation of ㈣ 丨 ^^ 丨 such as amino groups. These alkylations can be carried out by the reaction of an amine with an aldehyde in the presence of a reducing agent, such as sodium triethylsulfonium borohydride or hydrogen cyanohydride. The invention further proposes the preparation of a compound of formula (la), which converts a compound of formula (VI), wherein R5 is a carboxyl group and R1, R2, R3 and R4 are as defined in formula (I), and is converted into a compound of formula (la), wherein R1, R2, R3, R4 and R5 are as defined in formula (I).

An example of this conversion is shown in the synthetic schemes of Methods 1 to 3 below. The purpose of the method 1 can be carried out in a refluxing alcohol, such as a low-carbon enzyme such as ethanol or methanol, using an acid catalysis such as sulfuric acid or an acidic ion exchange resin. Esters can also be synthesized from equivalent alcohols in an inert solvent such as DMF or THF, and in the presence of a coupling reagent such as HATU or TBTU. The amidine in method 2 can be synthesized from equivalent amines, such as D MF in an emotional solvent, and the presence of a coupling reagent, such as 1,3-dicyclohexylcarbodiimide, 1- (3-di Methylaminopropyl) -3-ethylcarbodiimide, HATU or TB TU. The reduction of the acid group in the method 3 can be performed by a reducing agent such as dioxane or the acid is converted into an ester, which is then reduced to an alcohol with sodium borohydride. -33- 200410687 (29) Synthesis Process Method 1:

H〇 ~ R

〇 N 〇 b H

'N

R9-〇H

R

Ry R

(la) 〇

(VI) NHR7

Synthesis Process Method 3:

Wherein R1, R2, R3, R7, R9, R12 and R13 are as defined in formula (I). Another aspect of the present invention is to propose an intermediate compound of formula (VI), which can be used to prepare a compound of formula (I). Compounds of formula (VI) can be prepared as described in methods (a) and (b). Compound of Formula (VI) -34- 200410687 (30)

Ο

Among them: R1 is hydrogen, C02R7, NHCOR7, CN or halogen; R2 is nitrogen 'isS'OCi-6' pit group 'or or heterocyclic ring, where' yes, 2 or 3 are independently selected from N, O and S Heteroatom; and R3 is hydrogen or halogen; R6 is Cb6 alkyl group, which is 1, 2 or 3 independently selected from several groups, substituted by OC6 alkyl group OCi_6 alkylOH and NR12R13; R7 is CONHOC " alkyl OH, or C " alkyl is optionally 1, 2, 3 or 4 independently selected from hydroxy, substituted by OCu 垸 group and NR12R15 substituent, or R7 is phenyl or 5- or 6- A membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, which is a salt, a solvate or a solvate type of a salt thereof. The invention further relates to the use of the compound of formula (VI) as an intermediate, and can be used to prepare the compound of (I). Examples The present invention will be described in detail, and the following examples do not constitute a limitation of the present invention. All chemicals and reagents are used in the form obtained from suppliers. 1H and C nuclear magnetic resonance (NMR) spectra were recorded on a BRUKER DPX 400 (400 MHz) spectrometer using the following solvents and references. -35- 200410687

(31) NMBi TMS (0.0 ppm) & 13 (:, CDCl3i central front (77.0) ° CDeD # NMR 3.31 ppm (central peak) and uc 49 · 〇ppm (central peak). DMSO-d ^ H NMR 2.5 ppm (central peak) and 35.1 ppm (central octane). MS (ECI) a has been recorded on a Waters Alliance 2790 + ZMD spectrometer equipped with software Mass Lynx 3.5. Preparative HPLC on Waters HPLC, XTerra®Prep MSC8, 10 micron '19x300 mm, acetonitrile (20-80%) / 0.1MNH4〇Ae in 1% acetonitrile, 20 l / min. Fast column chromatography on silica gel 60 Carry out (2 3 0-400 mesh sieve). Examples Example 1 8-(1 fluorene-benzimidyl-2 -ylsulfenyl) -4 (1 fluorene)-π Kuiyi (i) 5-{[ 2- (lH-benzimidazol-2-ylsulfanyl) aniline;] methylene} -2,2-dimethyl-1,3 -dioxane-4,6 -difluorene with 2, A solution of 2-dimethyldioxane · 4,6-dione (300 mg) in trimethyl orthoformate (10 ml), stirred at reflux for 1 hour. Add 2- (1Η-benzimidazole-2 -Ylsulfanyl) aniline (500 mg) and heating was continued for another 2 hours. The solution was evaporated under vacuum and the residue was triturated with diethyl ether to The main title compound was a brown solid. (420 mg). MS: APCI (-ve) 394 (M-1). (Ii) 8- (1 fluorene-benzimidazol-2-ylsulfanyl)- 4 (1H) -quinolones trifluoroacetate 5-{[2- (111-benzimidol-2-ylthiolane) aniline] methylene oxide 2,2 · -36- 200410687

(32) Dimethyl-1,3-dioxane-4,6-dione (1.0 g) was added portionwise to the diphenyl ether (20 g) under reflux, and the resulting solution was at reflux temperature Stir for 15 minutes. The reaction was cooled to ~ 50 ° C and poured into stirred isohexane (100 ml) to produce a brown precipitate which was collected by filtration and dried under vacuum. The solid was purified with reverse-phase HP L C and dissolved with 75-0.5% 0.1% trifluoroacetic acid / methanol to give the title compound (16 mg). lU NMR d6-DMSO: (5 8.25 (1H? dd); 7.92 (1H? dd); 7.86 (1H? d); 7.39 (3H, m); 7.11 (2H, m); 6.13 (1H, d ) 5 M.pt. > 2 50 ° C. Example 2 8-[(5-Chloro_1H-benzimidazol-2-yl) sulfanyl] -4 (1H) -cynanone (1 ) 2,2-Dimethyl-5-{[2- (methylsulfanyl) aniline] methylene} -1,3-bisσ-4,6-dione 2- (methylsulfide ) Aniline (3.74 g) and 2,2-dimethyl-5-methoxymethylene-1,3-dihumane-4,6-dione (5.0 g) in acetonitrile (40 ml) The solution was stirred and stirred overnight under nitrogen. The reaction was evaporated under vacuum and the residue was triturated with diethyl ether to give the subtitled compound as a yellow solid (7.02 g). IH-NMR (CDC13): 5 11.85 (1Η, d); 8.68 (1Η, d); 7.53 (1Η, d); 7.37 (2H, d); 7.24 (1H, m); 2.47 (3H, s); 1.77 (6H, m) (Ii) 8- (methylsulfanyl) -4 (1 H) -fluorenone 2,2-dimethyl-5-{[2- (methylsulfanyl) aniline] fluorenylene } -1,3-Dioxane-4,6-dione (7.00 g) was added portionwise to the diphenyl ether (60 g) under stirring under reflux for 5 minutes. The resulting solution was stirred under reflux and stirred for another 1 minute. 5 minutes, then cool to 5. The reaction was poured into a stirred solution of iso-hexane (800 mL) to generate views of the title compound, a brown gum, which is then collected and dried under vacuum -37-200410687

(4.99 grams). MS :: APCI (-ve); 1 90 (M-1, 100%). (iii) Stir the solution of sodium 4-keto-1,4-dihydro-8-quinoline thiol sodium (240 mg) in liquid ammonia (50 ml) at _ 3 3 ° C to 8 A solution of-(methylsulfanyl) -4 (1 hydrazone) -p-quioxanone (1.0 g) in anhydrous tetrahydrofuran (5 ml) was gradually processed. The reaction was stirred for 30 minutes, then cooled with ethanol (1 ml) and allowed to warm to room temperature. The residue was dissolved in methanol (20 mL) and evaporated under vacuum to give a brown solid, which was triturated with diethyl ether and dried under vacuum (805 Mg). h-NMR (d6-DMSO): 5 7.86 (1H, d); 7.36 (1H, dd); 7.27 (1H, dd); 6.49 (1H, t); 5.68 (1H, d) 〇 ( W) 8-[(5-Chloro-1H-benzimidazol-2-yl) sulfanyl] -4 (1 H) -Wabinone 5-chloro-2-methanesulfonyl-1H-benzimidazole (0.3 g) (described in US Pat. 3480643), sodium 4-keto-1,4-dihydro-8-quinolinethiolate (0.35 g), acetic acid (0.3 ml), and isopropanol (2 0 ml) mixed and heated under reflux conditions overnight. The reaction mixture was concentrated under vacuum and water (5 ml) was added to the residue. The aqueous suspension was sonicated and insolubles were removed by filtration. Add dichloromethane (5 liters) to this material and repeat the sonication step. The insolubles were removed by filtration, and then treated with ethyl acetate (5 ml), sonicated and filtered again. The remaining solid was the title compound (0.05 g). MS: A PCI (+ ve) 32 8 (Μ + 1) ^ NMR (d6-DMSO) (5 8.29 (1H5 dd); 8.02 (1H? Dd); 7.83 (1H? D); 7.47-7.3 8 (3H5 m); 7.12 (1H? dd); 6.15 (1H, d); 3 · 32 (2H, br. s). Example 3 2-(4-S Isobase-1, 4-Two Mouse Junlin_ 8- Basic sulfur fe-based) -1 Η -Dongbiankou rice 嗤 -4 -End-38- 200410687

Methyl ester (i) 2-Methanesulfonyl-1 fluorene-benzimidazole-4-carboxylic acid methyl ester at 2-mercapto-1 fluorene-benzimidazole-4-carboxylic acid methyl ester (4.16 g) (see J Med. Chem. 1993, 36 (15), 2182) in a stirred solution of anhydrous acetone (100 ml), potassium carbonate (2.76 g) and methyl iodide (1.24 liters) were added. The resulting suspension was stirred at room temperature for 2 hours, then concentrated under vacuum, water (50 ml) was added and the mixture was acidified with a 1M hydrochloric acid solution. The resulting solution was washed with diethyl ether (2 x 50 ml), the aqueous extract was basified with a 1 M sodium hydroxide solution, and extracted with dichloromethane (3 x 50 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to 100 ml. The solution was cooled in an ice bath, and meta-chloroperoxybenzoic acid (70% purity, 9.86 g) was added, and the resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was washed with a saturated sodium bicarbonate solution (2 x 50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give the subtitled compound. Yield 4.52 charge. MS: APCI (+ ve) 2 5 5 (Μ + 1) 1 Η N MR (CD C13) (5 11.09 (1H, s); 8.12 (2H, t); 7.49 (1H, t); 4 · 04 (3H, s); 4.04 (3 H, s) o (ii) 2-(4-keto-1,4-dihydro-quinolin-8-ylsulfanyl) -1 H -benzene A solution of methyl benzimidazole-4-carboxylic acid methyl ester in 2-methanesulfonyl-1H-benzimidazole-4-carboxylic acid methyl ester (1.02 g) in anhydrous isopropanol (50 ml) Then, add 8-mirchi-1 Η-π-quinacene-4 -one sodium salt (1.07 g) and acetic acid (0.5 ml). The resulting suspension was stirred at 90 ° C for 4 8 hours, cooled and vacuumed The residue was partitioned between ethyl acetate (50 ml) and water (20 ml), and then extracted into a 1 M hydrochloric acid solution (2 -39- 200410687).

X 3 0 ml). The aqueous extract was neutralized with a 1 M sodium hydroxide solution, and then extracted with ethyl acetate (3 × 30 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The resulting solid was triturated with acetone and collected by filtration to give the title compound as a solid. Yield 0.01 g, MS: APCI (+ ve) 352 (M + 1) 〇4 NMR (3 99.9 8 MHz, DMSO) 5 12.86 (1H? S); 1 1.26 (1H, d); 8.29 (1H, dd ); 8.05 (1H, dd); 7.7 9-7.73 (2H? M); 7.66 (1H, d); 7.4 1 (1H, t); 7.18 (1 H, t); 6. 1 2 (1H D); 3.97 (3H, s), MP: > 250 ° C. Example 4 8-[(5-Chloro-1H-benzimidazol-2-yl) sulfanyl] -5 · nitro-4 (1H) -Iso (1) 5-[(2-fluoro- 5-nitroaniline) methylene] -2,2-dimethyl-1,3-diuridine_4,6-dione 2 fluoro-5 -nitroaniline (2 5.0 g) in acetonitrile ( 300 ml) solution, treated with 5- (methoxymethylene) -2,2-dimethyl-1,3-dioxane-4,6-dione (2 9.7 5 g), Stir for another 20 hours at room temperature. The solvent was removed under vacuum and the residue was triturated with 20% diethyl ether / isohexane (300 mL). The resulting light brown solid was collected by filtration and dried under vacuum. Yield: 49.0 8 g. 1H NMR CDC13: 5 11.47 (1H, d); 8.72 (1H, d); 8.3 6-8.34 (1 H, m); 8. 1 7-8 · 1 3 (1 H, m); 7 _ 4 1 (1 H, t); 1.7 8 (6 H, s) o (ii) 8-fluoro-5 -nitro-4 (1 H) -fluorenone 5-[(2-fluoro-5-nitroaniline (Methylene) methylene] -2,2-dimethyl-1,3-dioxane-4,6-dione, carefully added in portions to -40- ( 36) (36) 200410687

Diphenyl ether (600 ml). After the addition was complete, heating was continued for 10 minutes, and the reaction allowed it to cool to ~ 50 ° C. The dark solution was slowly poured into stirred isohexane (4 liters), and the resulting precipitate was collected by filtration. Repeated wet milling of the solid with dichloromethane (5 X 200 ml) yielded a dark brown solid which was then dried under vacuum. Yield: 20.21 g. MS: Apci (+ ve) 2 () 9 (m + i). (iii) 8-[(5-Chloro-1H-benzimidazol_2_yl) sulfanyl] _5_nitro, ih) ketopanone (46 mg) in ethanol (ml) was stirred, treated with 10 M sodium hydroxide solution (25 µl), and stirred for 10 minutes to produce a dark solution. 8. Fluoronitro-4 (ιη) -fluorenone (54 mg) was added and the reaction was stirred overnight at 100 ° C. The solvent was evaporated under vacuum and the residue was purified by reverse-phase HPLC using 75.5%. 〇1% trifluoroacetic acid in water / methanol dissolves to form the title compound. Yield 3 mg. lH NMR d6-DMSO: 5 8.15 (1H5 d); 7.92 (1H? d); 7.64 (1H, d); 7.51 (1H, d); 7.41 (1H, d); 7.16 (1H, dd); 6 23 (1H, d). 5-amino-8-[(5-chloro-1H-benzimidazole_2_yl) sulfanyl] -4 (1h) ^ quinone 8-[(5-chloro-1H-benzimidazole_ 2-Alkyl) sulfanyl] _5-nitro-4 (1H) _4 A suspension of the same (5.30 g) in cool acid (200 ml) at a pressure of 5 bar at 10% Pd / C (500 mg) was hydrogenated for 8 days. The suspension was filtered through a plug and the tray was washed with cool acid (5 x 200 ml). The filtrate was evaporated in vacuo (twice azeotropy with toluene), and the residue was triturated with diethyl ether (200 ml) to give a crude month: i: (3.20 g). A sample of crude amine (500 mg) was triturated with methanol (2X 5 mL) and diethyl ether (5 mL) and dried under vacuum. Yield: 3.05 mg. 4 200410687

(37) NMR d6-DMSO: 5 12.16 (1H5 s); 10.96 (1H9 s); 7.59-7.50 (3H, m); 7.31-7.28 (1H, s); 7.10 (1H, d), 6.41 (1H, d); 5.94 (1H, d); M.pt. > 28 0 ° C. Example 6 8-[(5-Chloro-1H-benzimidazol-2-yl) sulfanyl] -5-{[((2R) -pyrrolidinylfluorenyl] amino} -4 (1Η)-喳 喏Ketone (i) (2R) -2-[(1 8-[(5-chloro-1 H -benzimidazole-2-yl) -sulfanyl] -4-keto-1,4-dihydro -5-quinolinyl) amino] methyl} -1 -pyrrolidinecarboxylic acid tert-butyl ester N-boc-D-proline (23 3 mg) in acetic acid (5 ml) -Amino-8-[(5-chloro-1H-benzimidazol-2-yl) sulfanyl] -4 (1H) -quinone (200 mg) was treated and stirred for 1 hour. Add sodium triethylammonium borohydride (375 mg) and stir overnight. The mixture was evaporated under vacuum to produce a dark solid which was used without further purification. Yield: 320 mg, MS: APCI (+ ve) 526 (M + 1) (ii) 8-[(5-chloro-1H-benzimidazol-2-yl) sulfanyl] -5-{[(2R ) -Pyrrolidinylmethyl] amino} _4 (1H) _quinone (2R) _2-[({8-[(5-chloro-1H-benzimidazol-2-yl) sulfanyl]- 4-keto-1,4-dihydro-5-4 phosphono} amino) methyl] -1 -pyrrolidinecarboxylic acid tert-butyl ester (3 20 mg) in dichloromethane (20 ml) The solution was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 1 hour. The solution was evaporated under vacuum and the residue was purified by reverse phase HPLC (75-0.5% 0.1% trifluoroacetic acid in water / methanol The title compound can be produced as a yellow solid. Yield 48 mg. ^ NMRd6-DMSO: 5l 0.89 (lH, brs); 9.03 (lH, -42- 200410687

(38) br s); 8.67 (1H, br s); 7.72 (1H, d); 7.64 (1H, d); 7.43 (1H, d); 7.38 (1H, d); 7.13 (1H, m); 6.53 (1 H, d); 6 · 0 5 (1 H, d); 3.80 (1H5 m); 3.57 (2H9 m); 3.22 (2H? M); 2.15 (1H? M); 1.93 (2H , M); 1 · 68 (1H, m). Example 7 8-[(5-Chloro-1H-benzimidazol-2-yl) sulfanyl] -5-[(4-piperidinylmethyl) amino] -4 (1 Η)-4 fluorenone 5-Amino-8-[(5-chloro-1Η-benzimidazol-2-yl) sulfanyl] -4 (1Η) -Wazone (300 mg) and 4-methylamidino-1-piperazine A solution of tert-butyl picolinate (373 mg) in acetic acid was stirred at room temperature for 30 minutes. Add sodium triacetoxyhydroborate (560 mg) and continue stirring for 2 hours. The mixture was evaporated in vacuo and the residue was dissolved in dichloromethane (20 ml) and treated with trifluoroacetic acid (10 ml). After 1 hour, the reaction was evaporated under vacuum and the residue was dissolved in methanol (5 ml) and filled into a SCX silica (5 g) cartridge. The impurities were dissolved from the column with methanol (4 X 15 ml), and the product was dissolved with 10% ammonia water (S.G.0.88) in methanol (5 X 20 ml). The product eluate was evaporated in vacuo, and the residue was purified by reverse-phase HPLC using 50-0.5% 0.1% aqueous ammonia (S.G. 0.88) / methanol to separate the title compound as a green solid (34 mg): H NMR d6-DMSO: 5 10.77 (1H, brs); 7.62 (2H, dd); 7.40 (1H, d), 7.34 (1H, d); 7.06 (1H, dd); 6.36 (1H, d); 5 .99 (1H, d); 3.09 (2H5 m); 2.97 (2H5 m); 2.54 (2H5 m); 1.72 (2H5 m); 1.18 (2H, m) ° Mpt 230-232. . . Example 8 5-Chloro_2-[(4 · keto-1,4-dihydroquinolin-8-yl) sulfur] -1H-benzimidazole-4-nitrile • 43-200410687

(39) (i) 2-Amino-6-chloro-3.nitronitronitrile-2,6-dichloro-3-nitrobenzonitrile (100 g) suspended in methanol (1.2 L) 'and the mixture was saturated with ammonia. After 4 hours, the mixture was filtered to form 2-aminochloro.3-nitrofluorenitrile. Bright yellow solid (60 g) QiHNMRd6-DMS: (58.32 (lH, dd), 7.82 (2H, width s), 6.96 (lH, dd) ° (ii) 2,3-diamino-6-chloro Acrylonitrile 2-amino-6-chloro-3 -nitrocyanonitrile (8 g) in acetic acid: (100 ml) was treated with 5% pd / c (1 g) and the mixture was at 20 atmospheric pressure Hydrogenated for 16 hours. The catalyst was filtered to remove acetic acid and removed under vacuum to generate 2,3-diamine grave-6-chloronitrile. 1H NMRd6-DMSO: 5 6 · 63 (1H, ddl, 6.55 (1H, dd ), 5.73 (2H, wide s), 5.13 (2H, wide s). (Iii) 5-Chloro-2-phenyl-1H-benzimidyl 17 -Chlorobenzonitrile (6 g) was treated with 50 ° / 0 carbon disulfide in dimethylformamide A amine (100 ml) and the solution was heated in a sealed ball at 70 ° C for 16 hours. After cooling the ball Aerated and the mixture was poured into water (500 ml). The product was collected by filtration (8 g) ° H NMR d6-DMSO: (513 · 71 (1Η, width s), 1 3.1 1 (1Η, width s), 7.37 (2Η, s). (Iv) 5-Chloro-2- (methylthiobenzimidazine-4 -nitrile 5 -chloro-2-mercapto-1H_benzoimide " G) in acetone (150 ml) to solid Treatment with bulk potassium carbonate (8 g). The suspension was carefully wet-milled with methyl iodide (0.5 g per portion) at room temperature using 1 to determine the disappearance of the starting material and the appearance of the S-methylated material. Once all starting materials were consumed, the acetone was removed under vacuum and the residue was partitioned between water and ethyl acetate to give a brown solid (8 g). 4 NMR d6-DMS〇 at 90 ° C; 6 12.81 ( 1Η, width s), 7.86 -44- 200410687

(1H, width S), 7: 4 (2H, width m), 2.72 (3H, width 0. (v) 5-chloro-2- (methylsulfonyl) -1 H-benzimidazole-4_ Nitrile 5-Chloro-2- (methylthio) -1H-benzimidazole-4-carbonitrile (1 g) in methanol (10 ml) with Oxon (〇x〇ne) (4.68 g) in water (10 ml ), And disturbed overnight. The methanol was removed under vacuum and the reaction mixture was treated with aqueous sodium bicarbonate solution. The desired product was extracted with ethyl acetate, dried, and the solvent was removed under vacuum to produce 5-chloro. -2- (methylsulfonyl) -1Η-benzimidazole. 4-nitrile (1 g), iHNMRc ^ -DMSOi ^ 8.17 (1Η, d), 7.7l (1H, dd), 3.58 (3H , S). ~ (Vi) 5-Chloro-2-[[4-keto-1dihydroquinolin-8-yl] hard] qH-benzimidazole " 4 -Guess 5-chloro- 2- ( Methanesulfonyl) -1Η-benzimidazole-4-carbonitrile (0.2 g) and 4-keto-1,4-dihydro-8 · pyridinylthiolate (0.21 g) plus To isopropyl alcohol (10 ml) and glacial acetic acid (0.2 ml), and then heated in a sealed tube at 80 ° C overnight. After cooling to room temperature, the insoluble matter was removed from the reaction mixture, and this Followed by water, methanol and Wash with methyl chloride. The gray-brown solid remaining is the desired product (0.05 g, 18%). 4 NMR d6-DMS0, 5 12.87 (1H, brs); 11 · 40 (1H, brs); 8.35 (1H, d ); 8.12 (1H, d); 7.79 (1H, t); 7.62 (1H, d); 7.46 (1H, t); 7.39 (1H, d); 6.14 (1H, d) MS : APCI (+ ve) 353 (M + l). Mpt. 376 ° C (decomposition) Example 9 5 -Chloro-2-[(4-keto-1,4-dihydroquinolin-8-yl) sulfur Bu 1H-benzimidazonium methyl ester (i) 5-chloro-2 -fluorenyl-1 pyrene-benzimidazole · 4-carboxylic acid -45- 200410687

5 -Chloro-2 -fluorenyl: -ί Η -benzimidazole-4 -nitrile (0.5 g) was added to ethanol (5 ml) and 1 01V [sodium hydroxide solution (5 ml). The mixture was heated, refluxed for 24 hours, diluted with water (10 mL) and washed with ethyl acetate (25 mL). The aqueous layer was acidified with 2M hydrochloric acid, and the product was extracted with ethyl acetate. The ethyl acetate was washed with brine (20 liters). Drying over anhydrous magnesium sulfate, filtering, and concentrating under vacuum gave a light brown solid, 0.26 g (50%). 1U NMR d6-DMSO: 5 12.87 (1H, brs), 12.52 (1H? brs); 7.28-7.19 (2H, m); 3.33 (1H, brs). (ii) 5-Ga-2- (methylthio) -11 ^ _benzo-smell-4-lectic acid methylamidine 5-chloro-2-carboxyl_ίΗ-benzimidazole_4_carboxylic acid ( 0.26 g), potassium carbonate (0.62 g) and acetone (10 ml) were mixed and treated with methyl iodide (0.28 ml). The reaction mixture was stirred at room temperature for 1 hour, after which the thiol was methylated. The reaction mixture was concentrated under vacuum 'and methanol (3 ml) was added to the residue. The methanol suspension was passed through dcrodiscTM to remove potassium carbonate, and the filtrate was treated with concentrated sulfuric acid (4 drops). This was heated under reflux for 3 days and concentrated under vacuum. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give an oil (0.16 g, 62%). h NMR d6-DMSO: (5 12.95 and 12.62 (1H, 2brs); 7.68 and 7.49 (1H, 2brd); 7.27 (1H, d); 3.93 (13H, s); 2.69 (3H, s) (Iii) 5-Chloro-2- (methylsulfonyl) -1 H-benzimidazole-4-carboxylic acid methyl ester 5-Chloro-2- (methylthio) -1H-benzimidazole-4 -Methyl carboxylate (0.16 g) was added to methanol (10 ml), and the resulting suspension was treated with a solution of Oxon oxoneTM (0.61 g) in water (10 ml). The mixture was stirred at room temperature for 1 hour,- 46- 200410687

The methanol was removed by evaporation in vacuo. The remaining aqueous suspension was neutralized with a saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate. The ethyl acetate was washed with salt water, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to form a solid, which was ready for use without purification in the next step (0.15 g, 87%). (iv) 5-Chloro-2-[(4-keto-1,4-dihydroquinolin-8-yl) sulfur] -1H-benzimidazole-4 -carboxylic acid methyl ester The title compound was prepared from 5- Chloro-2-(fluorenylsulfonyl) -1 methyl-benzimidazole-4-carboxylic acid methyl ester, using the method of Example 8 (vi). 1H NMR d6-DMSO: 5 8.29 (1H, d); 8.03 (1H, d); 7.81 (1H, d); 7.49 (1H, d); 7.41 (1H? T); 7.19 (1H, d); 6.14 (1H, d); 3.93 (3H, s). Example 1 0 N-{5 -Chloro-2-[(4 · keto-1,4 -dihydroquinolin-8 -yl) sulfur] -1 H -benzimidazole-4 -yl} acidamine ( i) 5-Chloro-4-nitro-1H · benzimidazole-2-thiol 4-chloro-3-nitrobenzene-1,2-diamine (9.20 g) in anhydrous metformamide ( 30 ml) of the stirred solution, treated with carbon disulfide (25 ml), and stirred at room temperature for 72 poems. The reaction was poured into stirred distilled water (500 ml), and the resulting suspension was degassed with nitrogen. The mixture was filtered and the solid was washed with distilled water (2 x 50 ml) to give a brown solid which was dried under vacuum. Yield: 8.44 g, 1H NMR d6-DMSO: 5 13.23 (2H, brs), 7.42 (1 H, d); 7.35 (1H, d) ° (Π) 5-chloro-2- (methylthio) -4 -Nitro-1H-benzimidazole 5 -chloro-4 -nitro-1 pyrene -benzimidazole-2 -thiol (8.80 g) and potassium carbonate (5.29 g) in acetone (100 Ml) of a stirred suspension with methyl iodide (2.37 mmol-47- 200410687

L), and stirred at room temperature for 2 hours. The mixture was evaporated under vacuum, and the residue was treated with distilled water (200 ml). The mixture was extracted with ethyl acetate (2 x 2000 ml), and the organic layer was dried over anhydrous magnesium sulfate and evaporated under vacuum to give a brown solid. Yield 8.91 g. 1HNMRd6-DMSO: 5 13.40 (1H, brs), 7.64 (1H, d), 7.40 (1H, d), 2.71 (3H, s). (1 \ 5-Chloro-2- (methylthio) -111-benzimidazole-4-amine 5-chloro-2- (methylthio) -4-nitro-1H-benzimidazole (5.00 g) And iron powder (8.05 g) in a mixture of ethanol (105 ml), water (33 ml), acetic acid (11 ml) and formic acid (2 ml), and stirred under reflux for 2 hours. The mixture was filtered, and the filtrate was Evaporate in vacuo. The residue is treated with a saturated sodium bicarbonate solution (400 ml) and extracted with ethyl acetate (2X300 ml). The extract is dried over anhydrous magnesium sulfate and evaporated under vacuum to produce a dark solid. Rate: 3.71 g, 1HNMRd6-DMSO: (5 12.41 (lH, br, s); 6.95 (1H, d); 6.61 (1H, d), 5.23 (2H, brs), 2.68 (3H, s). (V ) N- [5-Chloro-2- (methylthio) -1 H-benzimidazol-4-yl] benzylamine 5-chloro- 2- (methylthio) -1 pyrene-benzimidazole_4- A stirred solution of amine (800 mg) in dichloromethane (20 ml) was treated with trichloromethane (1.3 ml) and triethylamine (1.57 ml). The resulting suspension was stirred at room temperature Overnight and evaporated under vacuum. The residue was suspended in methanol: water (3: 1,50 ml) And stirred at 60 ° C. for -night. The reaction was evaporated under vacuum and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was dried over anhydrous magnesium sulfate and vacuumed The residue was evaporated under reduced pressure and the residue was purified by flash column chromatography, dissolved with 20% ethyl acetate / isohexane. The title product was obtained as an orange solid. Yield 4300 mg. IHNMRcU-DMSC ^^ S ^ gClH. brs), -48- 200410687

(44) 10.25 (1H, brs), 8.07 (2H, m), 7.65-7.52 (3H, m), 7.47 (1H, d), 7.25 (1H, d), 2.68 (3H, s). (vi) N- [5-Chloro-2- (methylsulfonyl) -1 H-benzimidazol-4-yl] fluorenamine N- [5-chloro-2- (methylthio) -1 ′ -A stirred solution of benzimidazol-4-yl] amidamine (430 mg) in methanol (25 ml), treated with a solution of Oxon (1.33 g) in water (10 ml), and then in a chamber Stir for 24 hours at warm temperatures. The mixture was diluted with methanol (50 ml) and filtered. The filtrate was evaporated in vacuo to give a white-colored solid. Yield 300 mg. iH NMR d6-DMSO: 5 10.41 (1H, brs), 8.09 (2H, m), 7.74 (1H, d), 7.64 (1H, m) 5 7.59-7.53 (3H, m), 3.52 ( 3H, s). (vii) N- {5-chloro_2-[(4-keto-1,4-dihydroquinoline_8-yl) sulfur] -1H-benzimidazole-4 -yl} famidamine N_ { 5-Chloro-2- (methylsulfonyl) -1Η-benzimidazol-4-yl} benzylamidine (100 g) and 4-keto-1,4-dihydro-8-quinolinesulfide A suspension of sodium alkoxide (51 mg) in isopropanol (10 ml) was treated with acetic acid (2 drops, and then stirred overnight at 80 ° C. The reaction was evaporated under vacuum and the residue was passed through a fast column Purified by chromatography, eluting with 2% methanol / dichloromethane. The title compound was obtained as a yellow solid. Yield 18 mg, Mpt 280-285 ° C, 4 NMR d6-DMSO: δ 13.05 (1H, brs), 11.35 (1H, brs), 10.25 (1H, br s), 8.28 (1H, d), 8.05 (2H, br d), 7.81 (1H, s), 7.58 (2H, m), 7.45-7.15 (4H, m), 6.97 -6.80 (1 H, m), 6.13 (1H, m). Example 1 1 N-{5-chloro-2-[(4-keto-1,4-dihydroquinolin-8-yl) sulfur] -1 H-benzimidazole-4 -kib 2-furanamidamine-49- 200410687

(45) (i) N- [5-Chloro-2- (methylthio) -1 hydrazone-benzimidazol-4-yl] -2-furanamidine-prepared from 5 · chloro-2-as the title compound (Methylthio) -1 fluorene-benzimidazole-4 -amine (80 mg) and 2-furylformamidine chloride (1.1 ml), following the method of Example 10 (ν). Yield 300 mg. 1HNMRd6-DMSO: 5 12.69 (lH, brs), 10.15 (1H, brs), 7.95 (1H, d), 7.47 (1H, d), 7_35 (1H, m), 7.24 (1H, dd), 6_72 (1H , M), 2.68 (3H, s). (ii) N- [5-Chloro-2- (methylsulfonyl) -1Η · benzimidazol-4-yl] -2-furanamidine was prepared from N- [5-chloro-2- (Methylthio) -1H-benzimidazol-4-yl] -2-furanamidine (300 mg), following the method of Example 10 (vi). Yield 280 mg, iH NMR d6-DMSO: (5 10.34 (1H, s), 7.98 (1H, m), 7.72 (1H, d), 7.53 (1H, d), 7.37 (1H, dd) , 6.74 (1H, dd), 3. 17 (3H, s). (Iii) N-{5-chloro-2-[[4-keto_1,4-dihydroquinolin-8-yl) sulfur ] -1H-benzimidazole-4 -kib 2-furanamidine The title compound was prepared from N- {5-chloro-2- (methylsulfonyl) -1H-benzimidazole-4-yl} _2 · Furazolidamine, (100 mg), according to the method of Example 10 (vii). Yield 13 mg. 4 NMR d6-DMSO: 513.05 (lH, br, s), 11.35 (lH, br, s), 10.20 (1H, br, s), 8.28 (1H, d), 8.00 (2H, br, m), 7.81 (1H, m), 7.38 (3H, m), 7.22 (1H, m), 6.74 (1H , M), 6. 13 (1H, d). Example 1 2 7-[(5-chloro-1H-benzimidazol-2-yl) thio] -3- (methylsulfonic acid S & yl) -1 Η-41 Mouthwood -4 -month $ -50-200410687 (46) I invented the continuation sheet (i) 7-Fluoro 3- (methylthio) -4-nitro-1,3-dihydro- A stirred solution of 2H-W indole-2-one ·-(methylthio) ethyl acetate (28.5 ml) in dichloromethane (600 ml) at -7 ° C with thiosulfonyl chloride (1 6.5 ml) Dropwise processing, then Stir for 30 minutes. Add 2-fluoro-5 -nitroaniline (28 g) and N, N, N ', N'-tetrafluorenyl-1,8-diamine dropwise at -7 0 ° C. (46.2 g) in dichloromethane (450 ml), and the resulting red mixture was stirred: stirred for 2 hours. Triethylamine (2 9.8 ml) was added dropwise and stirring was continued for another 1 hour at -7 0 ° C. Remove the cooling bath and stir the reaction to room temperature overnight, then dilute with dichloromethane (500 ml) and wash with saturated brine (3 x 500 ml). Organics on anhydrous magnesium sulfate Dry and evaporate under vacuum to produce a red oil, which is soluble in glacial acetic acid (500 ml) and stirred at room temperature for 1 hour. The solution is evaporated under vacuum and the residue is treated with 2M hydrochloric acid (400 ml) Wet trituration. The solid was collected by filtration, triturated with diethyl ether (2 X 100 ml) and dried under vacuum. Yield 30.6 g. 1H NMR d6-DMSO: 5 11.51 (1H, s), 7.81 (1H , Dd) 5 7.48 (1H, t), 1.92 (3H, s).

(ii) 7-fluoro-3- (methylthio) _4-nitro-1H-pyridine 7-fluoro-3- (methylthio) -4-nitro-1,3_dihydro-2H-fluorene A solution of indol-2-one (0.2 g) in anhydrous tetrahydrofuran (10 ml) was treated with 1 M borane in tetrahydrofuran (1.6 6 ml). The reaction mixture was stirred (under nitrogen) at room temperature for 20 hours. Another aliquot (1.6 6 ml) of 1 M borane in tetrahydrofuran was added dropwise to the reaction mixture, and stirring was continued for 1 hour. The reaction mixture was cooled with a 2M mixture of hydrochloric acid and methanol, and then basified with a saturated sodium bicarbonate solution. The product was extracted with ethyl acetate (X 3), and the mixture extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. Generated solids to quickly -51-200410687

(47) Chromatographic purification 'uses 10% -20% ethyl acetate / isohexane as the eluent. The title compound was obtained as a brown-red solid. Yield: 8 丨 · 6 亳 g. !! h NMR d6-DMS〇: ά 7.808-7.729 (1H, dd); 7.729 (1H, s). 7.201 -7.13 9 (ih, t); 2.373 (3H, s), MS: APCI (-ve) 225 ( MH). (iii) 7-Fluoro-3-(methyl-continued S & yl) -4 -nitro-1 H -Hydroxy '7 -fluoro-3-(methylthio) -4 -nitro_ 1 η-p A solution of phlegm (0.463 g) in methanol was treated with Oxon's solution (i.6 weight, 2.02 g) in water, and the resulting suspension was stirred at 5 ° C for 30 hours. To the reaction mixture was added another equivalent of Oxon's solution in water, which was stirred at room temperature for 24 hours. Methanol was used in the real jade's and it was neutralized with an aqueous solution of sodium bicarbonate. The product was extracted with ethyl acetate (X 3), and the combined extracts were washed with saturated metabisulfite nalox solution and brine, and then dried over anhydrous magnesium sulfate. After removal of the solvent by filtration under vacuum, the subtitled compound was formed as a yellow solid. Yield: 43 9 pen grams, 1H NMR d6-DMSO: δ 8.363 (1H, s); 7.923-7.880 0H, dd); 7.394.7.332 (1H, t); 3 410 (3H, s). (1V) 5-chloro-2-{[3- (methylsulfonyl)> 4-nitroindole_7-yl] thiol 1H- ^ A solution of alcohol (0.356 g) in N-propanol was treated with hydrogen to oxidize paraffin (1.667M5 1.16ml). The resulting suspension was heated at reflux temperature for 0.5 hours, and then It is cooled. When 7_fluoro_3_ (methylsulfonyl 1 1 丨 wood 'is added and the resulting mixture is heated under reflux conditions for 20 J. After cooling, the reaction mixture is cooled with water and the product is again ethyl acetate Ester (X 3) extraction. The mixed organic layer was washed with 2M sodium hydroxide solution (X 7), -52- 200410687

(48) Dry over anhydrous magnesium sulfate, filter and evaporate under vacuum. The crude residue was purified by flash chromatography and dissolved in 20% ethyl acetate / dichloromethane to give the subtitled compound as a yellow solid. Yield: 200 mg. iH NMR 300 MHz d6-DMS: d 8.810 (1H5 s); 8.042 (1H? s); 7.89 3 -7.8 5 6 (1H, d); 7.772-7.744 (1 H, d); 7.65 1 -7.646 (1H , D); 7.575-7.546 (1 H? D); 7.321 (1H? Brd); 7.233-7.205 (2H? D); 3.503 (3H5 s). (v) 7_ [(5-Chloro-1H-benzimidazol-2-yl) sulfur] -3- (methylsulfonyl) -1 H-β 丨 indol-4-amine 5 -rat-2- { [3- (Methylhexyl) -4 • nitro-1Η-ρ5 丨 -7-yl] sulfur} -1Η-benzimidazole (100 mg) and vaporized tin (Π) (2 2 4 亳G) The ethanol suspension was heated at reflux for 7 hours. The reaction mixture was allowed to cool and half of the ethanol was removed under vacuum. The residue was poured into water, and then the saturated sodium bicarbonate solution was tested. The resulting mixture was filtered through a plug and the product was extracted with ethyl acetate (X 3). The combined organic extracts were washed with brine, dried over anhydrous tritium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by reverse-phase HPLC and purified at 75% -0.5 ° / 0.1. ΤΗΑ / 乙 月 膏 to give the title compound as a brown solid. Yield: 1 4.4 mg. iH NMR 400 MHz d6-DMSO: 5 7.703 (1Η, s); 7.382-7.378 (1H, s), 7.3 50-7.306 (2H, dd); 7.083-7.05 6 (1H? d); 6.562- 6.542 (1 H5 d); 3.254-3.229 (3H5 s); MS: APCI (+ ve) 3 9 3 (M + l). Example 13 5 -Chloro-2- 2-[[3- (methylsulfonyl-7-yl] sulfuryl)-1H-benzimid 53-200410687 (49) Tol-4-carboxylic acid methyl ester--( i) 3- (methylsulfonyl) -7- (methylthio) -4-nitro-1H-indole 7 -fluoro-3-(methylsulfonyl) -4 -nitro-1 Η -4 丨 A solution of indole (2.0 g) and sodium thiomethoxide (800 mg) in anhydrous methetamine (10 ml), stirred at 100 ° C for 2 hours. The mixture Pour into saturated brine (200 ml) and extract with ethyl acetate (3 x 100 ml). The extract is washed with saturated brine (3 x 200 ml), dried over anhydrous magnesium sulfate, It was then evaporated under vacuum to yield a yellow solid. Yield 2.06 g. 1H NMR d6-DMSO: 5 13.04 (1H, s), 8.19 (1H, d), 7.88 (1H, d) 5 7.33 (1H, d ), 3.42 (3H, s), 2.71 (3H, s). (Ii) 3- (methylsulfonyl) -7- (methylthio) -1H-Hi indol-4-amine 3- ( Methanesulfonyl) -7- (methylthio) -4-nitro-1H-indole (2.06 g) and iron powder (2.82 g) in ethanol: water: acetic acid: formic acid (70: 22: 7: 1 (100 ml), stirred under reflux for 2 hours. The mixture was cooled to At room temperature, it was filtered. The filtrate was evaporated under vacuum and the residue was triturated with a saturated acid-hydrogen-steel solution (50 ml). The resulting solid was collected by filtration and dried under vacuum at 70 ° C. Rate 2.00 g. 1H NMR d6-DMSO: 5 13.09 (1H, brs) 5 12.03 (1H, brs), 7.73 (1H, s), 7.15 (1H, d), 6.44 (1H, d) 5 5.79 (1H, brs), 3-26 (3H, s) 5 2.3 3 (3 H, s). (Iii) 3- (methylsulfonyl) -7- (methylthio) -1 HW indole 3- ( A stirred solution of methylsulfonyl) -7- (fluorenylthio) -1 H-pyridol-4-amine (2.0 g) in a 25% aqueous solution of hypophosphorous acid (100 ml) at 0 ° C It was treated dropwise with a solution of sodium nitrite (1.08 g) in water (15 ml). The resulting mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction was poured into brine -54- 200410687

(500 ml) and extracted with ethyl acetate (3 x 300 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under vacuum to produce a dark solid, which was purified by flash column chromatography and dissolved with 25% ethyl acetate / isohexane. The title product was obtained as a pale yellow solid. Yield: 730 mg. 4 NMR d6-DMSO: 5 12.28 (1H, br s), 7.94 (1 H, d), 7.68 (1H, dd), 7.27 (2H, m), 3.19 (3H, s), 2.56 ( 3H, s). (iv) 3- (Methanesulfonyl) -1H-pyridin-7-thiol sodium 3- (methylsulfonyl) -7- (methylthio) -1H-indole (200 mg) A stirred solution of liquid ammonia (10 ml) was treated dropwise with sodium (38 mg). The cooling bath was removed and the solvent was evaporated for 1 hour. The residue was quenched with ethanol (10 ml) and evaporated under vacuum to give a brown solid (180 mg). MS: APCI (_ve) 226 (M-1). 0) 5-Chloro-2-{[3- (methylsulfonamido) -1H-pyridin-7-yl] sulfur} -1H-benzobenzozol-4-methylcarboxylate 3- (methyl Sulfonyl) -1 hydrazone-indole-7-thiol sodium (180 mg) and 5-chloro_2- (methylsulfonyl) -1hydrazone-benzimidazole_4_carboxylic acid methyl ester (19 1 mg) of a stirred solution of isopropyl alcohol (10 ml), treated with glacial acetic acid (2 drops), and stirred overnight in a sealed tube at 100 ° C. The reaction was evaporated in vacuo and the residue was purified by flash chromatography using 30% ethyl acetate / isohexane to give the title product as a white solid. Yield: 28 mg. M.pt, 284-286 ° C. 4 NMR d6_DMSO: 5 12.87 (1H, br s), 12.35 (1H, brs), 8.00 (2H, m), 7.61 (lH, d), 7.55 (lH, d), 7.35 (1H, t), 7.22 ( lH, d), 3.95 (3H, d), 3.25 (3H, s). Real J column 1 4 -55- 200410687

5 -Chloro-2 [(3-methyl · 4-nitro-1 fluorene-indole-7-yl) sulfur] -1 fluorene-benzimidazole_ fluorene 7-fluoro-3-methyl-3- ( (Methylthio) -4-nitro-1,3-dihydro-2fluorene-indole_2-fluorene with 7-fluoro-3-(methylthio) -4 -nitro-1,3-dihydro- 2 hydrazone-oxindole-2 -one (5.0 g) and sodium carbonate (36 g) in acetone: dimethylformamide (2: 1, 200 ml) in a sandalwood suspension, 1 · 3 ml), and stirred at room temperature for 3 hours. The reaction was evaporated under vacuum and the residue was treated with distilled water (600 liters) and extracted with ethyl acetate (3 x 300 ml). The organic layer was washed with saturated brine (2 x 250 ml), dried over anhydrous magnesium sulfate and evaporated under vacuum to produce a red solid, which was then purified by flash column chromatography with 0- 丨% methanol / two Chloromethane dissolves. Yield: 1.15 g. 1H NMR d6-DMS: (5 11.70 (1H, brs), 7_79 (1H, dd), 7.51 (1H, 9), 1.76 (3H, s) 5 1_75 (3H, s). (Ii) 7 -Fluoro-3 -methyl-4_nitro_ih-indole7-fluoro_3-methyl-3- (methylthio) -4-nitro-1,3-dihydro-2H_indole _2_ Ketone (800 g) in anhydrous tetrahydrofuran (5 ml) was treated with methylboron dimethylsulfide complex (1.48 ml) under nitrogen, and then stirred under reflux for 2 hours. The reaction was poured into 1M hydrochloric acid (100 ml), and then extracted with ethyl acetate (3Xi50 ml). The organic extract was dried over anhydrous magnesium sulfate, and then evaporated to produce an orange solid, which can be purified by flash column chromatography. Dissolved with 5% ethyl acetate / isohexane. The title compound was obtained as an orange solid. Yield 41.10 g. 4 NMR CDC13: 5 8.48 (1H, br), 7.87 (1H, dd), 7.22 (1H, m), 6.92 (1H, t), 2.44 (3H, s). (Iii) 5-Ga- 2- [3-methyl-4-nitro-lH-il-l-7-yl] Sulfur] -1 H-benzimidazole sigma 5-chloro-1H-benzimidazole · 2-thiol (285 mg) in 2-methoxyethanol (6-56- 200410687

Ml) of the stirred solution, treated with an aqueous potassium hydroxide solution (0.93 ml, 1.67-M), and stirred at 130 ° C for 30 minutes. 7-Fluoro-3-methyl-4-nitro-ΙΗ-indole (300 mg) was added, and the solution was stirred at (30 ° C for 7 hours, and then evaporated under vacuum. The residue was taken in a flash tube. Purification by column chromatography and dissociation with 15-30% ethyl acetate / isohexane gave the title compound. Yield: 200 mg. M.pt. 252-253 ° C. 4 NMR d6-DMSO: 5 12.75 (lH, brs), 11.88 (1H, br s), 7.77 (1H, d), 7.5 5 -7.3 5 (4H, br, m), 7.17 (1H, dd), 2.3 1 (3H, s ) Example 1 5 — 7-[(5-chloro-1 fluorene-benzimidazole · 2-yl) sulfur] _ 3 -methyl-1 fluorene-4 indole-4 -amine The title compound was prepared from 5-chloro _2-[(3-methyl · 4-nitro-1Η-pyridol-7-yl) sulfur] -1Η-benzimidazole (160 mg), according to the method of Example 10, step 骡 (iv). Product Purified by flash chromatography, isolated with 20-30% ethyl acetate / isohexane. Yield 40 mg. M.pt, 229-230 ° C, iH NMR d6-DMSO: 5 11.80 (1H? Br d) 5 10.53 (1H5 br s)? 7.42 (1H5 m) 5 7.25 (1H, d), 7.07 (2H, m), 6.79 (1H, s), 6.25 (1H, d), 5.42 (2H, brs), 2.45 (3H, s). Example 1 6 5 -Chloro-2-{[3- (methylsulfinic acid Yl) -4-nitro-1H -indole-7-yl] sulfur} -1 hydrazone -benzimidazole (i) 7 -fluoro-3-(methylsulfinamidinyl) -4 -nitro-1 Η-Windole 7-fluoro-3- (methylthio) -4-nitro-1Η-oxindole (0.25 g) was added to methanol (8 ml), and then Oxon (0.68 g) was added to water ( 3 ml) solution. The reaction mixture was stirred at room temperature for 10 minutes. The methanol was evaporated from -57- 200410687 via vacuum.

The reaction mixture was removed and the remaining aqueous mixture was neutralized with a saturated, aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate, and insolubles were removed by filtration. The ethyl acetate was washed with brine 'and dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The obtained material, together with the previously removed impurities, was found to be the desired product by LC / MS. (0.2 g, NMR d6-DMSO: (? 13.30 (1H, br, s); 8.21-8.15 (2H? M); 7.32 (1H? T); 2.79 (3H, s). (Ii) 5-chloro- 2-{[3- (methylsulfinamilide) -4-nitro-1H-pyridin-7-yl] sulfur} -1 hydrazone-benzimidazole 5-chloro-1hydrazone-benzimidazole-2 -Mercaptan (0.15 g) in N-propanol (5 ml), treated with aqueous potassium hydroxide solution (0.5 ml, 1.67 M), followed by 7-fluoro-3-methylsulfinylene)- 1% 三 4-Nitro-1H-zole (0.2 g), and the mixture was heated overnight in a sealed tube at 90 ° C. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography to contain 0.1% three Ethylamine was dissolved in ethyl acetate. This gave the title compound, 0.2 g (59%). 1H NMR d6-DMSO: 5 8.16-8.11 (2H, m); 7.55 (1H, s); 7.49 (2H, dd); 7.20 (1H, dd); 2.82 (3H, s), MS: APCI (+ ve) 407 (M + 1) ° M.pt · 2 4 3-2 4 6 ° C ° Example 1 7 7- [(5-chloro-1 H -benzimidazole-2 -yl) sulfur] _ 3-(methylsulfinamilide) -1 H -indole-4-amine 5-chloro-2- {[3- (Methylsulfinylpyridinium 4j-Shoryl-1H-indole-7-yl] sulfur} -1H-benzimidazole (0.88 g) and iron powder (〇 16 g) in ethanol: water · acetic acid: formic acid (70: 22: 7: 1,10 ml) was heated at 70% for 1 hour. The mixture was passed -58- 200410687

(54) Filter through silica gel and concentrate the filtrate under vacuum. The residue was purified by flash chromatography-, eluting with ethyl acetate containing 0.1% triethylamine. This gave a white solid (0.06 g, 42%). VH NMR d6-DMSO: 5 12.05 (1H, d); 11.74 (1H, s); 7.64 (1H, d); 7.47 (1H, d); 7.43 -7.26 (2H, m); 7.08 (3H? dd); 6.54-6.48 (3H? m); 2.86 (3H5 s). MS APCI (+ ve) 377 (M + 1), M.pt. 245-247 ° C. Example 1 8 4 -Amino-7-[(5-chloro-1 fluorene-benzimidazole-2 -yl) sulfur] -1 hydrazone -oxindole-3 -aldehyde (i) 7-fluoro-3-(methyl Thio) -4-nitro · Lindole 7-fluoro-3 (methylthio) -4-nitro-1,3-dihydro-2H-pyridin-2-one (0.2 g) in anhydrous tetra A solution of dihydropropan (10 ml) was treated with 1 M methylboron / tetrahydrofram (1.66 ml). The reaction mixture was stirred at room temperature for 20 hours. An additional 1.6 M of a 1 M borane solution was added dropwise to the reaction mixture, and stirring was continued for another hour. The reaction mixture was quenched with a 2M mixture of hydrochloric acid and methanol, and then basified with saturated sodium bicarbonate. The product was extracted with ethyl acetate (X 3), dried over anhydrous magnesium sulfate, filtered, and evaporated under vacuum. The resulting product was purified by flash chromatography using 20% ethyl acetate / isohexane to elute. The title compound was obtained as a yellow oil. Yield: 69 mg (this reaction can also produce 7-fluoro-3- (methylthio) -4-nitro-1Η-4? Indole as a by-product). 4 NMR d6-DMSO: 5 7.42-7.37 (1H, dd), 7.26-7.1 9 (1H, t); 6.64 (1H, s); 4.98-4.95 (1 H, d), 4.04-3.97 (1H, m); 3.73-3.70 (1H, d); 1.97 (3H, s), MS: APCI (-ve) 227 (MH). (ii) 7-Fluoro-4 -nitro-1 H -oxindole 7 -fluoro-3-(methylthio) -4 -nitro-indoleline (650 mg) in methanol (30 mmol- 59- 200410687

(55) liters), treated with a solution of potassium peroxymonosulfate (3.6 g) in water (30 ml), and all stirred at room temperature for 72 hours. The methanol was removed under vacuum and the residue was neutralized with an aqueous sodium bicarbonate solution. The product was extracted with ethyl acetate (3 × 30 ml), and the mixture extract was washed with a saturated solution of saturated metabisulfite steel, washed with brine, and dried over anhydrous sulphuric acid. The solvent was removed under vacuum to give the subtitled compound as a light brown solid. Yield: 2 3 2 mg. MS: APCI (+ ve) 179 (M + H ^ HNMRJOO MHz d6-DMSO: ά 8.14-8.10 (1H, dd); 7.84-7.82 (1H, t); 7.22-7.16 (1H, t); 7.12-7 · 10 (1H, m). (Iii) 7-Fluoro-4 -nitro-1 H-ΘΙ indole-3 _ aldehyde phosphonium chloride (84 microliters) cooled to + 0 ° C in an ice / acetone bath Add anhydrous dimethylformamidine (300 μl) and stir all for 10 minutes. Add 7-fluoro-4 -nitro-1 硝基-4 indole (150 mg) to the reaction mixture Metformamide (600 μl), and slowly warm all to 20 ° C. After stirring at room temperature for 3 hours, the reaction was cooled with ice and then added with 2 M sodium hydroxide Solution (5 ml). The aqueous solution was extracted with ethyl acetate (10 ml). The pH value of the aqueous phase was adjusted to 6 with dilute hydrochloric acid, and extracted with ethyl acetate (20 ml). The mixed organic extracts were dried in water. Dry over magnesium sulfate and evaporate under vacuum to give the subtitled compound as a dark yellow oil (150 mg). IH NMR d6-CDCl3: 5 10.55 (1H, s), 8.27 (1H, s); 8.18- 8.15 (1H, m); 7.10-7.04 (1H, m), MS: APCI (-ve) 207 (Ml). (Iv) 7-[(5-chloro-1H-benzene Benzimidazol-2-yl) thio] -4-nitro-1H-W indol-3-aldehyde 5-chlorobenzimidazole-2-thiol (200 mg) in N-propanol (10 ml) with hydroxide 4A treatment (0.9ml, 1.67M), plus 7-fluoro-4-nitro-1H-pyridine-60- 200410687

_ 3-aldehyde (150 mg). All were heated at 90 ° C for 15 hours, and stirred with-. The solvent was removed under vacuum and the residue was taken up in ethyl acetate (20 ml) and washed with sodium bicarbonate solution. The organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was purified by flash chromatography, eluting with 50% ethyl acetate / isohexane to give the subtitled compound as an orange solid. Yield: 20 mg. MS: APCI (-ve) 3 7 1/3 73 (M-1). (v.) 4-Amino-7-[(5-chloro-1H-benzimidazol-2-yl) sulfur] -1H-wormworm-3-aldehyde 7-[(5 · chloro-1 fluorene-benzene Benzimidazole-2 -yl) sulfur] -4 -nitro-1 fluorene -oxindole 3 -aldehyde (15 mg) and iron powder (180 mg) in ethanol: water: acetic acid: formic acid (70: 22: 7: (10 ml) was stirred for 1 hour under reflux. The mixture was cooled to room temperature and filtered. The filtrate was evaporated in vacuo, and the residue was dissolved in ethyl acetate (5 liters) and washed with a saturated sodium bicarbonate solution (5 liters), and then brine (5 ml). The organic phase was dried over anhydrous magnesium sulfate and evaporated under vacuum. The residue was purified by flash chromatography and dissolved in 500 / ethyl acetate / isohexane 'to give the title compound as a pale yellow solid. Yield: 7 mg. 4 NMR d6-DMSO: 5 12_22 (1Η, br s); 12.08 and 12.04 (1Η, 2x br s-2 isomers); 9 7〇 (1H, s); 8.22 (1H, s); 7 48 / 7.46 and 7.3 5 / 7.3 3 (1 only, 2 / (1-2 isomers); 7.5 3 and 7.3 5 (111, 2 / 8-2 isomers); 7.33 / 7.31 (1Η, d ); 7.15 / 7.13 (1Η, d), 6.91 (2Η, s); 6.49 / 6.47 (1H, d), MS: APCI (-ve) 3 4 1/343 (Ml). Example 1 9 7- [(5-Chloro-l-pyrene-benzimidazole-2 _yl) thibu 3 _ (methylsulfonyl-H _indole) The title compound was prepared from 5-chloro-2 -methanesulfonyl-l-pyridine -benzo Imidazole (19 1 halo grams) and 3-(methylsulfonyl) _ 丨 Η-indole-7 _ sodium thiolate, according to the actual -61-200410687

(57) Example 1 The method of step (4). The product was purified by flash column chromatography,-isolated at 30%-ethyl acetate / isohexane. Yield 28 mg. Mpt284-286 ° C. 1H NMR d6-DMSO: 5 12.44 (1H, brs), 8.00 (2H, m), 7.59 (1H, d), 7.47-7.3 2 (3H, m) 5 7_ 12 (1H, d); 3.24 ( 3H, s). Example 2 0 4-[(5-Chloro-1H-benzimidazole-2 · yl) sulfur] -1,3 · dihydro-2H-benzimidazole-2 -fluorene (i) 4 -hydroxy-1,3 -Dihydro-2 hydrazone -benzimidazole-2 -one p- 2,3-diaminophenol (10.34 g) in a stirred solution of dimethylformamide (100 ml), 1. Γ-carbonyldiimidazole (1 3.4 8 g) was added dropwise to keep the temperature below 60 ° C. The solution was stirred for an additional hour. The solvent was removed under vacuum, and the residue was dissolved in ethyl acetate and washed with 2M steel hydroxide solution (2X). The alkaline solution was mixed, acidified to pH 2 with 1M hydrochloric acid, and extracted with ethyl acetate (4X). The ethyl acetate portion was mixed, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give a brown solid. The solid was washed with diethyl ether to give the subtitled compound. Yield: 6 g. 4 NMR d6-DMSO: 5 10.42 (1H, s); 10.31 (1H, s); 9.46 (1H, s); 6.72 (1H, t); 6.44-6.40 (2H, m). (ii) 6- (2 · Keto-2,3-dihydro-1H-benzimidazol-4-yl) dimethyl thiamine formic acid and dimethyl thioaminoformyl chloride (2.46 g) Add dimethylformamidine (20 ml) dropwise to 4-hydroxy-1,3-dihydro-2H-benzimidazol-2-one (3 g) and cesium carbonate (6.5 g) Formamidine (100 ml). The reaction was stirred for 2 hours, the solvent was removed under vacuum, and the residue was partitioned between water and -62- 200410687

(58) in ethyl acetate. The organic phase was washed with 2M sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under vacuum to form a solid. This was triturated with acetone to give the subtitled compound. Yield: 1 g. 1H NMR d6-DMS〇: 5 10.90 (1Η, s); 10.72 (1Η, s), 6.90 (1Η, t); 6.80 (1H, d); 6.63 (1H, d); 2.36 (3H, s); 3.30 (3H, s). (iii) S- (2-Methenyl-2,3-Yifeng-1 Η-Dongmenwei mouth-sat-4 -yl) -methylthiocarbamate 0- (2 · keto-2 , 3-Dihydro-1Η-benzimidazole-4-yl) · Dimethylthiocarbamate (0.9 g) in a stirred solution of diphenyl ether (10 ml), heated at reflux temperature 2 hours. The cooled suspension was added to isohexane (200 ml), and the precipitate was separated by filtration. The solid was washed with ethyl acetate and acetonitrile, and the combined washings were concentrated under vacuum. The resulting solid was purified by flash column chromatography and dissolved in 5% methanol / dichloromethane to give the subtitled compound. Yield 0.2 g. 1U NMR d6-DMSO: (geometric isomer) 5 1 0.9 0-1 0.6 9 (2 Η, m); 7.01-6.65 (3H, m); 3.0 8-7.87 (6H, m). (iv) 4-Mercapto-1,3-dihydro-2H-benzimidazol-2-one 12M sodium hydroxide (0.27 ml) was added to S- (2-keto-2,3-dihydro-1M- A solution of benzimidazol-4-yl) dimethylthiocarbamate (0.155 g) in water (5 ml) and heated to reflux temperature for 2 hours. The solution was cooled to room temperature, and then acetic acid was added to adjust the pΗ value to 5. The precipitated solid was isolated by filtration to give the subtitled compound. Yield 0.076 g. MS: APCI (+ ve), 167 (M + 1). (ν) 4-[(5 · Chloro-1H-benzimidazol-2-yl) sulfur] -1,3-dihydro-2H-benzimidone-2 -one in 5-chloro-2-(methyl Sulfofluorenyl) -1H-benzimidazole (0.106 g) in isopropyl-63-200410687

To a stirred solution of alcohol (10 ml), 4-mercapto-13-dihydro-2H-benzimidazol-2-one (0.076 g) was added. The mixture was heated at reflux temperature for 18 hours. The solvent was removed under vacuum, and the residue was purified by reverse-phase HPLC and separated with 75-0.5% 0.1% aqueous NH〆) / acetonitrile to give the title compound. Yield 0.03 0 g. 1 2H NMR d6-DMSO: δ 12 · 39 (1H, brs); 11.04 (1H, brs); 10.90 (1H, s); 7.45 (1H, brs); 7.40 (1H, brs); 7.13 (2H, d); 7.08-6.99 (2H, m); MS.APCI (+ ve) 317 (M + 1). Example 2 1 -64- 1 7-[(5 -Chloro-1H -benzimidazol-yl) sulfur] -2 -keto-2,3 -dihydro-1H -benzimidazine-5 -metanoic acid ( i) 7- (Chlorosulfonyl) _2_keto-2,3-dihydro-1H-benzimidazole-5-carboxylic acid chlorosulfonic acid (4 ml) was carefully added to keto-2,3_ Dihydro-1H-benzimidazoline-5-slim-line form (1 · 0 g) (see justus Liebigs Ann · Chem; 2 8 9 6 (2 9 1); 3 2 8), and the mixture in Heated at 1000 ° C for 8 hours. The reaction mixture was cooled to room temperature and then carefully added dropwise to cold methanol (30 ml, -40 ° C). After the addition was complete, water (10 mL) was added and the product was dried with ethyl acetate (X3). Ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to give the subtitled product as a light brown solid, 1.2 g (83%). 4 NMR d6-DMSO: 5 13.43 (1Η, brs); 10.92 (1Η, s); 9.72 (1H, s); 7.82 (1H, s); 7.41 (1H, s). 200410687

(60) Heat for 1 hour. The reaction was cooled to room temperature, and then water was added, followed by 2 M sodium hydroxide solution (20 ml). The mixture was washed with ethyl acetate and acidified with 2M hydrochloric acid (20 ml). The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to produce the desired product (0.3 g, 79%) ° ^ NMR d6-DMSO: 5 12.45 (1H? Brs); 11.11 (1H? S); 11.04 (1H, s); 7.55 (1H, s); 7.28 (1H, s); 5.38 (1H, brs). (Mountain) 7-[(5-Chloro-111-Benzobenzo-2-yl) thio] -2-fluorenyl-2,3-dihydro_1H-benzimidazole-5-carboxylic acid From 7-fluorenyl-2-keto-2,3-dihydro-1H-benzimidazole-5 -carboxylic acid (91 g) and 5-chloro-2 -methanesulfonyl-1 fluorene-benzene Benzimidazole (100 mg), using the method described in Example 20 (ν). Yield 70 mg, ^ NMR d6-DMSO: 5 11.51 (1H? Brs); 11.20 (1H? Brs); 7.79 (1H? Brs); 7.57 (2H? Dd); 7.46 (1H? Dd); 7.22 (1H dd); 2.35 (2H, s); M.pt 326-3 3 0 ° C. Example 2 2 7- {[5-Chloro-4- (methoxycarbonyl) -1 H-benzimidazol-2-yl] thio} -2-keto-2,3-dihydro-11 ^ benzo The imidazole-5-fatty acid title compound was prepared from 7-fluorenyl-2-keto-2,3-dihydro-1 hydrazone-benzimidazole-5-carboxylic acid (74 mg) and 5-chloro-2- ( Methanesulfonyl) -l-benzimidazole-4-carboxylic acid methyl ester (100 mg), using the method described in Example 20 (ν). Yield: 75 mg. 4 NMR d6-DMSO: (5 12.86 (1Η, brs); 11.43 (1Η, brs); 11.14 (1H? Brs); 7.78 (1H5 brs); 7.57 (2H? Brs); 7.24 (1H, d); 3.94 (3H, s). Example 2 3 65- 200410687

7-[(5-Chloro-4-[(2-oleethoxy) carbonyl] -1H-benzimidazol-2-yl) thio-2-keto-2,3-dihydro-1H-benzo Imidazole-5-carboxylic acid (i) 5-chloro-2- (methylthio) -1Η-benzimidazole-4-carboxylic acid 5-chloro-2-((thiothio) -1Η-benzimidazole-4 -Nitrile (2.4 g) was refluxed in 10 M sodium hydroxide (40 ml) for 16 hours. The reaction was cooled, and then cooled to pH 7 with 2M hydrochloric acid, and a precipitate formed. The carboxylic acid was isolated by filtration and air-dried to give a brown solid (2 g). MS: APCI (-ve) 242 (M-1). (ii) 5-Chloro-2- (methylthio) -1 hydrazone-benzimidazole-4-carboxylic acid 2-hydroxyethyl ester 5-chloro- 2- (methylthio) -1 hydrazone-benzimidazole- 4-carboxylic acid (2 g) was suspended in thionyl chloride (50 ml) and refluxed for 2 hours. The excess of thionyl chloride was removed under vacuum and the solid residue was treated with ethylene glycol (20 mL). The mixture was heated at 80 ° C for 2 hours. It was cooled and partitioned between ethyl acetate and water. The vinegar was separated by drying the organic layer, and the solvent was removed under vacuum. MS: APCI (-ve) 286 (M-1). (iii) 5-Chloro-2- (methylsulfonyl) -1Η-benzimidazole-4-carboxylic acid 2-hydroxyethyl 5-chloro-2 · (methylsulfonyl) -1Η-benzo Imidazole-4-carboxylic acid 2-hydroxyethyl ester (1 g) in methanol (10 ml) was treated with Oxon (4.68 g) in water (10 ml) and stirred overnight. The methanol was removed under vacuum and the reaction mixture was treated with an aqueous sodium bicarbonate solution. The desired product is extracted with ethyl acetate, dried, and the solvent is removed under vacuum to form 5-chloro-2- (methylsulfonyl) -1H-benzimidazole-4-carboxylic acid 2-hydroxyethyl. Ester (1 g), MS: APCI (-ve) 317 (M-1), (iv) 7-{{5-chloro- 4-[(2-hydroxyethoxy) carbonyl] _1H-benzimidazole- 2-yl} Thib 2-keto-2,3-dihydro-11 benzimidazole-5-carboxylic acid. The title compound was prepared from 5-chloro-2- (methylsulfonamido) -1hydrazone-benzimidazole-4-carboxylic acid 2-hydroxy-66-200410687 (62) the invention of Wenglang ethyl ester (0.16 g) and __7-Mirroryl-2-keto_2,3_dihydro-1H-benzimidazole-5 < carboxylic acid (0.16 g) was refluxed together in isopropanol for 4 hours. The product was isolated once cooled (0.1 g) and separated by filtration. 1H NMR d6-DMSO: 5 11.45 (s, 1Η), 11.15 (s, 1Η), 7.8 (s, 1Η), 5.56 (s, 1H), 7_55 (s, 1H), 4.4 (t, 2H), 3.71 (t, 3H). Example 24 7-[(5 -Chloro-1Η-benzimidazole-2 -yl) sulfur] -2-keto-2,3-dihydro-1-1-benzimidazole-5 -carboxylic acid methyl ester Prepared as described in Method 1 ~ (i) 7- (Chlorosulfonyl) -2-one- 2,3-dihydro-1 hydrazone-benzimidazole-5-carboxylic acid chlorosulfonic acid (4 ml) was carefully added To 2-keto-2,3-dihydro-1H-benzimidazoline-5-formate (1.0 g) (see Justus Liebigs Ann. Chem .; 1 8 9 6, (2 9 1 ); 3 2 8) and the mixture was heated at 100 ° C for 8 hours. The reaction mixture was cooled to room temperature, and then carefully added dropwise to cold methanol (30 ml,-40 ° C). After the addition was complete, water (10 ml) was added and the product was extracted with ethyl acetate (X3). Ethyl acetate was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give the subtitled product as a light brown solid, 1.2 g (83%), iH NMR d6-DMSO: (5 13.43 (1H, brs); 10.92 (1H, s); 9.72 (1H, s); 7.82 (1H, s); 7.41 (1H, s). (Ii) 7-Mercapto-2-keto-2,3- Dihydro-1 H -benzimidazole-5 -carboxylic acid 7-(chlorosulfonyl) -2-keto-2,3-dihydro-1 hydrazone · benzimidazole-5 -carboxylic acid (0 · 5 G) was added to tetrahydrofuran (10 ml), and the resulting mixture was treated with triphenylphosphine (1.66 g) in portions. Water (2 ml) was added and the reaction mixture was heated at 50 ° C for 1 hour. Reaction The mixture was cooled to room temperature, and water and 2 M hydroxide-67-200410687 (63) sodium solution (20 ml) were added. The mixture was washed with ethyl acetate and acidified with 2 M hydrochloric acid (2 (X ml)). Extracted with ethyl acetate, dried on anhydrous sulfuric acid steel, filtered and concentrated under vacuum to produce the desired product. (0.3 g, 79%). 咜 NMR d6-DMSO: 5 12.4 5 (1Η, brs); 11.11 ( 1H, s); 11.04 (1H, s); 7.55 (1H, s); 7.28 (1H, s) 5.38 (1H, brs). (Iii) 7-[(5-Chloro-1H-benzimidazole-2-yl) thiazole 2-keto-2,3-dihydro-1 hydrazone-benzimidazole- 5-carboxylic acid '5-chloro-2- (methylsulfonamido) -1 醯 -benzimidazole (100 mg) is described in US Xin P · t · 3 4 8 0 6 4 3) in isopropanol (10 ml) of a stirred solution, added 7-yl-2 -keto-2,3-dihydro-1 hydrazone · benzimidazole-5 -carboxylic acid (91 mg). The mixture was heated at reflux temperature for 18 The solvent was removed under vacuum and the residue was purified by reverse-phase HPLC 'elute with a 0.1% aqueous NHd) / acetonitrile gradient to give the title compound. Yield: 70 mg. 4 NMR d6-DMSO: 5 11,51 (1H, brs); 11.20 (1H, brs); 7.79 (1H, brs); 7.57 (2H, dd); 7.46 (1Η, dd); 7. · 22 (1Η, dd); 2.35 (2Η, s). (iv) 7-[(5-Chloro-1H-benzimidino-2-yl) thio] yl-2,3 · dihydrolubenzimidazole-5 -carboxylic acid methyl ester

Dowex H + added to 7-[(5-chloro-1H-benzimidazole_2_yl) sulfur] _2-_yl-2,3-dihydro-1H-benzimidazole-5-carboxylic acid (100 mg, 0.28 mmol) in methanol (50 ml). The reaction mixture was refluxed overnight, after which Dowex H + was filtered off and washed with DMF and CH2C12. The filtrate was concentrated and purified by flash column chromatography (CH2Cl2 / MeOH 5: 1) to give 12 mg (12%) of the title compound. hNMRdpDMSCH 3.81 (3H, s), 7.12 dd), 7.40 (1H, m), 7.47 (1H, m), 7.55 (1H, d), 7.77 (1H, d) -68- 200410687

10.75 (1H, s), 11.18 (1H, s), 12.60 (1H, s "13CNMR- (DMSO-d6)" 52.2, 106.7, 108.4, 109.5, 110.1, 120.1, 121.8, 122.6, 124.5, 129.0, 130.4, 130.8, 137.2, 155.2, 165.7 MS (ECI) m / z 3 7 5 and 3 77 (M + 1). Example 2 5 7-[(5 -Chloro-1H -benzimidazole_2 -yl) sulfur]- 2 -Keto-2,3 -dihydro-1H -benzimidazole-5 -Ethyl leptate T2S04 added to 7-[(5-chloro-1H-benzimidazol-2-yl) sulfur]- 2-keto-2,3-dihydro-111-benzimidazole_5-carboxylic acid (95 mg, 0.26 mmol) & ethanol (20 ml). The reaction was refluxed overnight, neutralized, Concentration and purification by precipitation from MeOH / CH2Ch (1: 3) solution yielded 56 mg (55%) of the title compound. 4 NMR (DMSO_d6: U 1.29 (3H, ti〇, 4.27 (2H, q) , 7.12 (1H, d), 7.42 (2H, m) 5 7.5 5 (1 H, d), 7.76 (1H, d), 11 · 18 (1H, s) 5 11.53 (1H, s) , 12.53 (1H, s). 13C NMR (DMSO-d6): 814.2, 60.8, 106.6, 110.2, 121.8, 122.9, 129.0, 130.8, 137.2, 155.2, 165.1, MS (ECI) m / z 3 89 and 39 1 (M + 1). Example 2 6 7-[(5-Chloro-1H-benzimidazol-2-yl) sulfur ] -2 -Keto-2,3-dihydro-1fluorene · benzimidazole-5-metanoic acid (100 mg, 0.27 mmol) was dissolved in 2 ml of anhydrous DMF. N-light ethyl was added Morphine (327 mg, 0.27 mmol), HATU (308 mg, 0.81 mmol), diisopropyldiethylamine (285 μl '1.6 mg), and the resulting mixture is at 6 Stir at 0 ° C for 6 days. Remove the falling agent and the resulting yellow solid was purified by preparative reverse phase HPLC with -69- 200410687.

This gave 33 mg (260/0) of the title compound. 1HNMR (DMSO-d6): (52.34- (4H, m), 2.69 (2H, m) 5 3.61 (4H, m), 4.35 (2H, m), 7.13 (1H, d), 7.33 (1H, d), 7.48 (1H, d), 7.57 (1H, s) 5 7.98 (1H, s), 13C NMR (DMSO-d6): 553.7, 56.8, 62.3, 66.5, 107.3, 110.5 , 122.2, 123.1, 126.1, 129.1, 130.8, 134.6, 137.4, 151.2, 155.6, 159.3, 165.5, MS (ECI) m / z 474 (M + l). Example 27 7 _ [(5-chloro-6- Fluoro-111-benzimidazol-2-yl) sulfur] -2-keto-2,3-dihydro-1H-benzimidazine-5-junic acid is prepared as described in Method 1. 5_chloro-6 -Fluoro-2- (methylsulfonyl) -iH-benzimidazole (0.53 g, 2.14 mmol) and 7-Dynyl-2-keto_2,3_dihydro-1H-benzimidazole -5-carboxylic acid (0.45 g '2.14 mmol) was dissolved in a THF / 2-propanol solution (30 ml, 1: 1), refluxed for 2 hours and concentrated under vacuum. The crude mixture was partitioned between 1 μ NaOH ( Aqueous solution) and CH2C12. The pH of the aqueous phase was adjusted to about pH 3. The precipitate was filtered off, washed with water and dried. The solid was refluxed in a CH2Cl2 / MeOH solution (3: 1), filtered off and washed with CH2C12 , And then dried to produce 0.79 g (97%) of the title compound. 4 NMR (DMSO_d6): (5 7.53 (2H, m), 7.56 (1H, s), 7.74 (1H, s), 11.23 (1H, s), 11.46 (1H, s), 12.78 (1H, s), MS (ECI) m / z 379 and 381 (M + 1). Example 2 8 7-[(5-methoxy-1 ^ 1-benzimidazol-2-yl) sulfur] -2-one-2, 3-Dihydro-1 hydrazone · Benzimidazole-5 -carboxylic acid is prepared as described in Method 1. Starting from 5-methoxy-2-(methylsulfonyl) -1 hydrazone--70- 200410687

Benzimidazole (0. 8 g, 2.14 mmol) and 7-mercapto-2-one, 2,3-dihydro-1H-benzimidazole-5-acid (0.45 g, 2.14 mmol) Mol) yields 0.75 g (98%) of the title compound. 4 NMR (DMSO-d6): 5 3.75 (3H, s), 6.81 (1H, dd), 6.96 (1H, s), 7.36 (1H, d), 7.54 (1H, s), 7.72 (1H, s) , 11.19 (1H, s), 1ΐ · 50 (1H, s), MS (ECI) m / z 3 57 (M + 1). Example 29

7 _ [(5 -Bromo · 1 Η -benzimidazole-2 -yl) sulfur] _ 2 -keto-2,3 -dihydro-1 Η -benzimidazole-5 -carboxylic acid — according to method 1 Describing preparation. Starting from 5-bromo-2- (methylsulfonyl) -1Η-benzimidyl (344 mg, 1.25 mmol) and 7-mercapto-2-keto-2,3-dihydro-1Η- Benzimidazole-5-carboxylic acid (263 mg, 125 mmol) yielded 344 mg (68%) of the title compound. 1HNMR (DMSO-d6): 57 · 64 (2H, dd), 7.89 (1Η, s) 5 7.96 (1Η, s), 8.04 (1Η, s), 11.49 (1Η, s), 11.80 ( 1Η, s), MS (ECI) m / z 406 (M + 1).

Example 3 0 7-[(4-Bromo-6-fluoro-1H-benzimidazole-2 -yl) sulfur] -2 -keto-2,3_dihydro • 1 pyrene-benzimidone-5- Acidification was prepared as described in Method 1. Starting from 4-bromo-6-fluoro-2- (methylsulfonamido) -1fluorene-benzimidazole (3 37 mg, 1.15 mmol) and 7-acid-2-keto-2,3 -Dihydro-1H-benzimidazole-5-carboxylic acid (263 g, 1.25 mmol) yields 369 g (76%) of the title compound. iHNMRCDMSO-cU): ^ 7.34 (1Η, s) 5 7.42 (1H, s), 7.54 (1H, s), 7.62 (1H, s), 11.09 (1H, s), 11.43 (1H, s) 5 MS (ECI) m / z 424 (M + 1). -71-200410687

(67) Example 3 1 7-[(5-Chloro-1H-benzimidazole-2 · yl) sulfur] -N_ [2- (4-morpholine-renylethyl) -2 -keto-2 , 3 -dihydro-1H-benzimidazole-5-Betamine is prepared as described in Method 2.

Hunigs test (47 μl, 0.27 halo) added to 7-[(5_chloro-1H -benzimidone_2-yl) sulfur] -2 -keto_2,3-dihydro-1H- Benzimidamine · 5-Falate (90 mg '0.25¾ Mol) and 4- (2-aminoethyl) morphine (36 μl, 0.27 mmol) in DMF (4.0 mL) at ambient temperature Next, stir the solution. TBTU (88 mg, 0.27 moles), 〇ΒΤχί 20 (34 milligrams, 0.25¾ moles) and Htinig's test (47 µl, 0.27 moles) were added. After 2.5 hours of stirring, the reaction mixture was concentrated under vacuum and purified by flash column chromatography (CH2Cl2 / MeOH 5: 1-2: 1) to yield 95 mg (81%) of the title compound. 1H NMR (DMS〇-d6): 52.38 (4H, ⑷, 2.42 (2H, to, 3.35 (2H, m), 3.53 (4H, tv), 7.13 (1H, d), 7 3 5 (1 H, m), 7.47 (1H? M)? 7.55 (1H5 s)? 7.73 (1H? S) 5 8.41 (1H? Tr) 5 U · 15 (1H, S), U · 26 (1H , S), 12 · 45 (1H, s), MS (ECI), m / z 47 3 and 47 5 (M + 1) ° 3 2 methylamino] ethyl-2- 7-[(5-chloro _1H-benzimidazole-2-yl) succinate [3_diketo-2,3-dihydro-1H-benzimidazole-5_guineal method 2: • 17 halo) plus To 7-[(5-chloro-1H-benzo

Hunig's base (30 microliters of imidazo-2-yl) sulfur] -2 -S isoyl-2,3-dimg, 0.14 mmol) and n, N-dihydro-1H-benzimidazole Carboxylic acid (π methylethylenediamine (17 μl, 0.1 7-72. 200410687

Mol) in DMF / acetonitrile (4.0 ml, 1: 3) at ambient temperature-. After 10 minutes, TBBT 0 (56 mg, 0.17 mol), ΗΒΒΤΗ 20 (21 mg, 0.17 mol) and Hun igfs base (30 μl, 0.17 mol) were added. 4 hours later add additional The amount of n, N-dimethylethylenediamine 'TBTU, Η0ΒΤχΗ20 and Hunig's test, and the reaction mixture was stirred: stir overnight, then concentrated under vacuum and purified by flash column chromatography (CH2Cl2 / MeOH 2: 1-1 : 3) 58 mg, 86%) of the title compound can be produced. 4 NMR (DMSO-d6) ... 2.14 (6H, s), 2.35 (2H, to, 3.30 (2H, q), 7.06 (1H, dd), 7.36 (1H, d) 5 7 · 42 (1H, d) 5 7 · 52 (1H, s), 7.71 (1H, s), 8.37 (1H, tr), MS (ECI) m / z 431 and 433 (M + 1). Example 3 3 4- [(5 -Chloro-1H-benzimidazolyl) sulfur] _6-[(4-methylpiperidin-1-yl) carbonyl] -1,3-digas-2H-benzopyrtr-2- Same method 2:

Hunig's test (108 μl, 0.62 mmol) was added to 7 _ [(5_chloro_ ^ • benzimidazol-2-yl) sulfur] -2-one-2-_2,3_dihydro_1Η • A solution of benzimidazole 5-carboxylic acid (150 g, 0.42 ¾ mole) and fluorenyl pipen (51 µl, 0.46 mol) in DMF (4.0 ml) at ambient temperature. After 5 minutes, TBTO (147t g, 0.46 mmol), hBTxH20 (56 mg, βQ mmol) and Hunig's base (85 μl, 0.46 mmol) were added. After stirring for 3 hours, the reaction mixture was concentrated under vacuum and purified by flash column chromatography twice (CH2Cl2 / MeOH 5: 1-2: 1) to yield 51 mg (28%) of the title compound. lHNMR (DMS 0-d6): m4 (3H, s), 2.22 (4H, m), 3.45 (4H, m), 7.03 (1H, d) 5 7.08 (1H, d), 7 l4 (1H , Dd), 7 4ι -73- 200410687

(lH, m), 7.48 (lH, m), 11.07 (lH, s) 5li.30 (1H, s), i2.66- (1H, s) 5 MS (ECI) m / z 443 and 445 (M +1) 〇 Example 3 4 7-[(5 -Chloro-1H -benzimidino-2-yl) sulfur] -N -methyl-2-keto-2,3 -dihydro-1 fluorene -benzene A solution of benzimidazole-5 -carboxamide methylamine 8.0M in ethanol (76 microliters, 0.61 mmol) was added to 7-[(5-chloro-1fluorene-benzimidazole · 2 · yl) sulfur]- 2-keto-2,3-dihydro-1fluorene-benzimidol-5-carboxylic acid (200 mg, 055 mmol) and Hunig's base (144 μl '〇_ 83 mmol) In DMF (4 10 ml) at ambient temperature. After 5 minutes, TBTU (147 mg, 0.61 mmol), OBTB × 20 (56¾ g, 0.55¾ Mol) and Hunig's base (106 μl, 0.61 mmol) were added.

. The reaction mixture was stirred overnight, concentrated under vacuum, and then precipitated from CH2Cl2 / Me0H / valley to yield 102 mg (49%) of the title compound. NMR (DMSO-d6): 0 2.73 (3H, d) 5 7.12 (1H, d) 5 7.39 (2H, m), 7.55 (1H, s), 7.72 (1H, s) 5 8.42 (1H , D), 11.16 (1H5 s), 11.34 (1H, s), 12.44 (1H, s), MS (ECI) m / z 374 and 376 (M + 1). Example 3 5 7 [(5Chloro-1Η · benzimidazole_2_yl) sulfur] _n_ (2_hydroxyethyl) _2_keto-2,3-dihydrobenzimidazole_5_carboxamide, HUnig's test (106 μl, 0.61 mmol) was added to 7 _ [(5_chloro · ih_benzomide 2 groups) Shier] -2 -keto_2,3_dihydro] H • A solution of benzimidazole_ 5_ carboxylic acid (2 ⑽ gross grams 0.55 moles) and ethanolamine (37 μl, 0.61 mmoles) in DMf (5.0 ml) at ambient temperature +. After 5 minutes, add Ding Ca (0.60 Mok), 〇〇ΒΤχΗ20 (75 mg, 0.55 Mo-74 · 200410687 (70) 1 miscellaneous turning ear) and Hunig's test · (106 microwells, 0.61 millimoles). The reaction mixture was concentrated after 2 hours, and then purified by precipitation from CH2Cl2 / MeOH solution to yield 115 mg (51%) of the title compound. 4 NMR (DMSO-d6): 5 3.29 (2H, q) 5 3.49 (2H, tr) 5 7.10 (1H, d), 7.38 (1H, m), 7.45 (1H, m) 5 7.59 (lH, s) 5 7.7 7 (1 H, s), 11.19 (1H, s), 11.32 (1H, s), 12.43 (1H, rs), MS (ECI) m / z 404 and 406 (M + 1). Example 3 6 4-[(5-Chloro-1H-benzimidazole-2 · yl) sulfur] -6- (piperin-1-ylcarbonyl) / l, 3-dihydro-2H-benzimidazole-2 -Ketodihydrochloride

Hunig's base (158 μl, 0.92 mmol) added to 7 _ [(5_chloro-111-benzimidazole · 2-yl) sulfur] -2-keto-2,3-dihydro-1 pyrene-benzene Benzimidazole_ 5-chitoic acid (300 g, 0.83 mmol) and tert-butyl piperonate (170 mg, 0.92 mmol) in DMF (6.0 ml) at ambient temperature Of solution. After 5 minutes, TBTU (294 mg, 0.92 mmol), OBTX × 20 (112 mg, 0.83 mmol) and Hunig's base (158 µl, 0.92 mmol) were added. The reaction mixture was concentrated after 2 hours and purified twice by flash chromatography (CH2Cl2 / Me0H10: 1) to give 23 3 mg (54%) of the product protected by B oc-. The base was redissolved in methanol (8 mL) and treated with 4M HC1 / diethyl ether (1 mL) overnight, concentrated, and washed with methanol / diethyl ether (1: 1) to yield 185 g (44%) of the title compound. . h NMR (DMSO-d6): 6 3.09 (4H, m), 3.73 (4H, m), 7.16 (1H, d), 7.23 (1H, dd), 7.31 (1H, d), 7.48 (1H, d), 7.55 (1H, d), 9.39 (2H, s), 11.22 (1H, s), 1 1.36 (1H, s) 0 -75- (71) (71) 200410687

Example 3 7 Benzimidazole · octyl) sulfur] _2-keto_2,3_dihydro_ih-benzimidol-5-double acid amine To "... Chloro- ^ benzomide 2 groups) Shicagua] -2 -keto-2,3--oxy-1H -benzimidazole-5_chinic acid (200 g, 0.55¾ Mo Ear) and ammonium chloride (89 mg, 17 mmol) DMF (4.0 ¾ liter) at ambient temperature. After 5 minutes, tbtu (196 mg, 0.61 mmol), hBTXH20 (75 G, 0.55 mmol) and HUnig, s (192 μl, 1 "mmol). The reaction mixture was concentrated after 2 hours and purified on a short silica gel column (CH2Cl2 / Me0H 5: 1). ) Concentrated product was precipitated from warm Me Η Η solution to yield 70 mg (35%) of the title compound. 4 NMR (DMSO-d6): 5 7.12 (1Η, dd), 7.24 (1H, s), 7.42 (2H, m), 7.59 (1H, s) 5 7.78 (1H, s), 7.97 (1H, s), 11.14 (1H, s), 11.29 (1H5 s), 12.52 (1H, s), 13C NMR: 109.4, 121.6, 127.2, 127.6, 130.2, 135.7, 155.3, 167.0 MS (ECI) m / z 3 60 and 3 62 (M + 1) o Example 3 8 7-[(5 -Chloro- 1H-benzimidazol-2-yl) sulfur] -N -[2- (2-Hydroxyethoxy) ethyl] -2-S isopropyl-2,3-dihydro-1H-benzimidone-5-carboxamide TBTU (104 mg, 0.32 mmol ), HOBTXH20 (44 mg, 0.32 mmol) and! 1 ^ 1 ^ '3 base (57 μl, 0.32 mmol) were added to 7-[(5-chloro-1 pyrene-benzo Imidazole 2-yl) sulfur] -2-keto-2,3-dihydro-1 hydrazone-benzimidazole-5-carboxylic acid (100 mg, 0.28 mmol) in DMF (3 ml) in the environment To the solution at temperature. After 5 minutes, add 2- (2.aminoethoxy) ethanol (3 3 micro-76- 200410687

Liters, 0.32 millimoles :), and the reaction was concentrated after 15 minutes. The crude mixture was purified by precipitation from a methanol-ethyl acetate (1: 4) solution to yield 14 g (11%) of the title compound. 4 NMR (DMSO-d6): 5 3.40 (4H, m), 3.48 (4H5 m)? 7.11 (1H, d), 7.42 (2H? M)? 7.57 (1H? S)? 7.75 (1H, s), 8.52 (1H, tr) 5 11.15 (1H, s), 11.33 (1H, s), 12.43 (1H, s). MS (ECI) m / z 448 and 450 (M + 1). Example 3 9 4 _ [(5-Chloro-1H-benzimidazol-2-yl) sulfur] -6-{[4_ (2-hydroxyethyl) piperidin-1-yl] postyl}}-1,3 -Dihydro- 2H-benzo Weijun-2-pyrene with TBTU (104 μg, 0.32 mmol), HOBTXH20 (44 mg, 0.32 mmol) and Hiinig, s-base (57 μl, 0.32 Mol) to 7 _ [(5-chloro-1 fluorene-benzimidazole-2 -yl) sulfur] -2 -keto-2,3 -dihydro · 1 Η · benzimidazole-5 _ carboxylic acid (100 mg, 0.28 mmol) in a solution of DMF (3 ml) at ambient temperature. After 5 minutes, the 1- (2-transethyl) peak- (33 μl, 0.32 mmol) was added, and the reaction mixture was concentrated after 20 hours. The crude mixture was purified by precipitation with methanol-acetic acid ethanol (1: 3) solution to yield 46 mg (3 5%) of the title compound. 1HNMR (DMSO-d6): 5 3.03 (4H, m), 3.34 (2H, m ), 3.65 (2H, m) 5 7.10 (1H, s), 7.14 (1H, m), 7.37 (2Η, m), 7.48 (1Η, m), 11.11 (1Η, s), 11.33 (1Η, s), 12.57 (1H, s), 13C NMR (DMSO-d6) J41.7, 51.4, 54.9, 58.3, 109.1, 1 1 1. 1.8, 1 2 1 .9, 1 25.8, 1 3 0.7, 1 34.3, 1 5 5.8, 168.5, MS (ECI) m / z 3 75 and 377 (M + 1) ° Example 40 7-[(5-chloro · 1Η-benzimidazole-2_yl) sulfur] _2_one-N-4-piperidin-4-yl- 2,3- -77- 200410687

Dihydro-1 pyrene-benzimidazole-5-Jun Si amine dihydrochloride

TBTU (104 mg, 0.33 mmol), 〇BTXH20 (44 mg, 0.32 mmol) and 1 ^ 11 丨 8, base (57 μl, 0.32 mmol) were added to 7- [ (5-Chloro-1Η-benzimidazol-2-yl) sulfur] -2-keto 2,3-dihydro-1Η-benzimidazole-5-carboxylic acid (100 mg, 0.28 MM) in DMF (3 ml) at ambient temperature. After 5 minutes, tertiary butyl 4-aminopiperidine-l-carboxylic acid (67 mg, 0.32 mmol) was added. The reaction mixture was stirred overnight and concentrated. The crude mixture was dissolved in methanol / diethyl ether (1: 1, 2 mL), treated with 4MHC1 / diethyl ether (1 mL) overnight, concentrated 'and purified by precipitation from a methanol / diethyl ether (1 ·· 4) solution— 'Produce 37 mg (26%) of the title compound. 1 η NMR (DMSO-d6): 5 1.75 (2Η, m), 1.90 (2Η, m), 2.95 (2Η, m) 5 3.26 (2Η, m), 4.03 (1Η, m), 7.20 (1Η, dd), 7.45 (1Η, d), 7.51 (1H, d), 7.62 (1H, s), 7.84 (1H, s), 8.52 (1H, d), 8.96

(2H, s), 11.21 (1H5 s), 11.37 (ih, s)? 13C NMR (DMSO-d6): 528.1, 42_2, 44.5, 104.6, 109.7, 122.4, 126.6, 127.6, 130.4, 135.9 , 150.4, 155.3, 164.8, MS (ECI) m / z 443 and 445 (M + l) ° Example 4 1 N- (3-aminopropyl) -7-[(5-chloro-11 * 1_benzene Benzimidazol-2-yl) thiazole 2-keto-2,3 -monoazine-1H -benzotitu-5-diamine dihydrochloride TBTU (104 mg, 0.32 mmol), h. BTXH20 (44 mg, 0.32 mmol) and Htinig's base (57 μl, 0.32 mmol) were added to 7-[(5_chloro-1H-benzimidazole_2_yl) sulfur] _2-keto- 2,3_dihydro] H-benzimidazole-5-carboxylic acid (100 mg, 0.28 mmol) in DMF (3 ml) at ambient temperature -78- 200410687

under. After 5 minutes, tert-butyl N- (3-aminopropyl) carbamate (58 mg, 0.3 2 mmol) was added, and the reaction mixture was stirred overnight and then concentrated. The crude mixture was purified by precipitation from a methanol-dichloromethane (1: 1) solution. The dried precipitate was treated with 4 M H C 1 / diethyl ether (1 ml) overnight. It was concentrated again and washed with diethyl ether to give 63 mg (46%) of the title compound. 1 Η NMR (DMSO-d6): (5 1.79 (2Η, m), 2.79 (2Η, m), 3.30 (2Η, m), 7.21 (1H, dd), 7.46 (1H, d), 7.53 (1H, d), 7.62 (1H, d), 7.82 (1H, d), 7.96 (3H, s), 8.74 (1H, tr), 11.27 (1H, s), 11.40 (1H, s), MS (ECI) m / z 417 and 419 (M + 1). Example 4 2 7-[(5-Chloro-1H-benzimidazol-2-yl)] thio-2-one -N- [3- (2-ketopyrrodoline-1-yl) propyl] -2,3-diazide-111-benzopyridine-5-amino-6 TBTU (104 mg, 0.32 Mol), H0BTXH20 (44 mg, 0.32 mol) and Htinigfs— (57 μl, 0.32 mol) added to 7-[(5-chloro-1 Η-benzimidazole-2-yl) sulfur ] ··· keto · 2,3-dihydro-1Η-benzimidazole-5 · carboxylic acid (100 mg, 0.28 mmol) in DMF (3 ml) at ambient temperature. After 5 minutes, add 1-(3-aminopropyl) -2-p ratio (4 7 µl, 0.3 2 mmol), and the reaction mixture was stirred overnight. The reaction mixture was then concentrated, and then from methanol-dichloride Purification by precipitation in methane (1: 2) solution yielded 73 mg (54%) of the title compound. 4 NMR (DMSO-d6): 5 1.68 (2H, m) 1.89 (2H, m ), 2.19 (2H, tr), 3.19 (4H, m), 3.32 (2H, m), 7.1 (1H, m), 7.35 (1H, m), 7.46 (1H, m), 7.56 (1H, s), 7.73 (1H, s), 11.11 (1H, s), 11.33 (1H, s), 12.57 (1H, s), 13C NMR (DMSO-d6): 5 17.5, 26.8, 30.4, 36.9, 46.3, 109 4 -79- 200410687

119.0, 121.5, 126.7, 127.8, 130.3, 155.3, 165.1, 173.9, MS (ECI) m / z 48 5 and 487 (M + 1). Example 4 3 4-[(5-Chloro-1H-benzimidazole-2-yl) sulfur] (hydroxymethyl) q, dihydro-2 fluorene-benzimidazole-2-one TBTU (104 ^; g '0.32¾ mole) and Hiinig's test (57 μl, 0.32 Φ mole) to 7-[(5-chloro-1H-benzimidone_2_yl) sulfur] · 2-keto_2, A solution of 3-dihydro-1H-benzimidazole-5 -carboxylic acid (100 mg, 0.28 mmol) in DMF (3 L) at ambient temperature. After 10 minutes, the reaction mixture was diluted with methanol. Add NaBH4 (20 mg '0.54 mmol) and stir the reaction mixture for 1.5 hours. Ethyl acetate and 0.5 M H C 1 were added, and the layers were separated. The aqueous phase was washed with ethyl acetate. The combined organic phases were washed with saturated nhco3 (aqueous solution), dried (Mg S04), filtered and concentrated. The crude mixture was purified on Prep-HPLC to give 27 mg (29%) of the title compound. lH NMR (DMSO-d6): 5 4.46? (2H, s)? 7.02 (1H? s)? 7.06 (1H, d), 7.11 (1H, dd) 5 7.3 9 (1 H, d), 7.45 (1H, s), 10.84 (1H, s), 13C NMR (DMSO-d6): (5 62.6, 105.9, 108.6, 121.5, 124.9, 125.8, 130.5, 131.9, 136.1, 155.3, 162.3, MS (ECI) m / z 3 47 and 3 49 (M + 1) °. Pharmacological evaluation of compounds JNK-1 kinase filtration assay Compounds were tested for inhibition of jNK-1 by kinase filtration assay. Test compounds were dissolved in 10 mM; DM (DMSO). Compounds were reused to make serial dilutions in DMS 0. Diluted compounds were further added to -80- 200410687

Dilute in 10-fold-kinase buffer solution (50 Mm MOPS, pH 7.2, containing 0.1%, ν / ν) β-mercaptoethanol to generate compounds in the kinase buffer solution plus 10% (ν / ν) DMS A solution with a final concentration of 0. Five microliters of each compound dilution was added to each well of a 96-well plate, in duplicate. Add 5 μl of kinase buffer solution plus 10% (v / v) DMSO, and replace the compound in the control holes (0% inhibition) and background holes (100% inhibition). 25 μl of 15% (w / v) trichloroacetic acid (1/8) containing 100 M m AT P was added to the background hole (100% inhibition). Add 20 microliters of ATH-2 protein substrate to each well; a mixture of magnesium chloride 'unlabeled ATP; and 32P-labeled ATP, so the final concentration is 0.2 / zMATF-2; 10 mM magnesium chloride; 1 // MATP and 0.1 / z (i32p-ACP. 25 microliters of JNK-1 mixture (0.1 micrograms / well) was added to start the reaction. The final reaction volume was 50 microliters. The kinase reaction was reduced to 21. (: Incubation for 60 minutes The reaction was further added by adding 25 microliters of 15% (w / v) TCA containing 100 mM ATP. The precipitate was allowed to form for 10 minutes, and then filtered on a 96-well GF / C single-filtration membrane. Each filter was Wash approximately ten times with 10 ml of water. The filter discs were dried at 30-40 ° C for 60 minutes. 25 microliters of liquid scintillation liquid was added to each hole, and the discs were sealed in packard T 〇pc 〇unt micro The radioactivity was counted on a disc scintillation counter. The compounds exemplified here were active in the above screening at submicromolar concentration levels. The abbreviation lists DMSO dimethylsulfoxide MOPS 3-[N-morpholinyl ] -Propanesulfonic acid • 81-200410687 (77) JNK c-Juft N-terminal kinase MAP mutants-activated protein LPS month polysaccharide TNF a cell movement Tumor necrosis factor between IL1 Aescin -1 ATF activated transcription factors ATP gland

Thl type 1 T helper cell MMP matrix metalloproteinase TCA trichloroacetic acid HOBT 1 -hydroxybenzotriazole hydrate TBTU 0 · (1Η-benzotriazol-1-yl) -N, N, N ,, N,- Tetramethyltungsten tetrafluoroborate HATU 0- (7-Azbenzotriazol-1-yl) -N, N, N'N'-tetramethyltungsten hexafluorophosphate

Htinigk base N, N-Diisopropylethylamine DMF Metformamide THF Tetrahydromethane M. P t Melting point -82- 200410687

(78) Fluorophosphoric acid'salt

Htinig ^ base N, N-diisopropylethylamine DMF dimethylformamidine THF tetrazine. P t Shaodian point -83-

Claims (1)

200410687 Patent application scope R1 is hydrogen, CHCHR6, CCR6, C02R7, NHCOR7, CN or halogen; R2 is hydrogen, halogen, CN, OCm alkyl, or 5- or 6-membered heterocyclic ring, which contains 1, 2 or 3 independently selected from N Heteroatoms of 0 and S; R3 is hydrogen or halogen; R4 is hydrogen, OH, NH2, N02 or NHR8; R5 is hydrogen, COR9, CHO, CH2OR10, OH, OCu alkyl, NH2, NW1, NHCONR10Rn, NHCOR10, CONR12R13, CONHR7, R7, or R4 and R5 plus a carbon atom attached to it form a 5-, 6-, or 7-membered pyrimidine ring; R6 is a Cm alkyl group, which is 1, 2 or 3 independent Selected from hydroxy, OCl_6 alkyl, OCu alkylOH and NR12R13; R7 is CONHOCm alkyl OH, or Cm alkyl is optionally 1, 2, 3 or 4 independently selected from hydroxy, 0 C i_ 6 alkyl And substituted with a substituent of R'1 2 R 13 or 200410687 R7 is phenyl or 5-or 6-membered heterocyclic ring, containing 1, 2, 3 or 4 侗 heteroatoms independently selected from N, 0 and S; R8 is COR14 or (CH) nQ, where η is 1, 2 Or 3, and Q is NR15R6 or 5-, 6- or 7-membered saturated heterocyclic ring, containing 1, 2 or 3 heteroatoms independently selected from N, X and S, at least one of which must be N, except when Q When it is a non-N-linked heterocyclic ring, η may be only 1; R9 is a hydroxyl group or an OC ^ alkyl group, which may be substituted by a 5- or 6-membered heterocyclic ring, wherein the ring contains 1, 2 or 3 independent Heteroatoms selected from N, O and S; R1G and R11 are independently selected from hydrogen and alkyl, and optionally substituted with 1, 2 or 3 substituents independently selected from hydroxyl, OCl-6 alkyl and NR12R13; R12 And R13 are independently selected from hydrogen and Cj_6 alkyl, or R12 and R13 together form a 5- or 6-membered heterocyclic ring, which contains 1, 2 or 3 heteroatoms independently selected from N, 0 and S, and the ring If necessary, it may be substituted by one or more substituents independently selected from hydroxyl, keto, Cu alkyl, OCu alkyl, and Cu alkyl OH; R14 is hydrogen or Cu alkyl; R15 and R16 are independently selected from hydrogen and Ci_6 alkane Base; A is 5- or 6-membered saturated, or 5- or 6-membered aromatic A ring containing, if necessary, one or more heteroatoms independently selected from N, O, and S, which contains more than one C = 0 group, and the ring may optionally have one or more independently selected from Ci-6 alkyl groups, S02Ci .6 Alkyl, SOCI.6 Alkyl, CO2H and CHO substituted with substituents in the form of salts, solvates or their solvates. 200410687 2. The compound according to item 1 of the scope of patent application, wherein: R2 is hydrogen, halogen, CN, or 5- or 6-membered heterocyclic ring, which contains 1, 2 or 3 heterocycles independently selected from N, O and S Atom; R5 is hydrogen, COR9, CHO, CH2OR1G, OH, OCb6 alkyl, NH2, NR10Rn, NHCONR10Rn, NHCOR10 or R4 and R5 plus the carbon atom attached to it can form 5-, 6- or 7- Ramine ring; R6 is Ci-6 alkyl group, which is substituted by 1, 2 or 3 substituents independently selected from hydroxy, OCl-6 alkyl group and NR12R13; R9 is hydroxyl group or OCu alkyl group; and R12 and R13 are independently selected from hydrogen and Cu alkyl. 3. The compound according to item 1 of the scope of patent application, wherein R 1 is hydrogen, CN, CO2CH3, CO2CH2CH3, CO2CH2CH20H, halogen or MHCOR7, wherein R7 is furyl or phenyl. 4. A compound according to any one of claims 1 to 3, wherein R3 is hydrogen. 5. A compound according to any one of claims 1 to 3 in the scope of the patent application, wherein R4 is hydrogen, HN2, N02 or NHR8, and R8 is CH2-exopyrridine. 6. The compound according to item 5 of the application, wherein R4 is NHR8, and R8 is CH2-piperidine. · 7 · The compound according to any one of claims 1 to 3, wherein R5 is hydrogen or COR9, and R9 is a hydroxyl group. 8. A compound according to any one of claims 1 to 3, wherein R5 is CONR12R13, CONHR7 or R7. 200410687 9. The compound according to any one of claims 1 to 3 of the scope of the patent application, wherein _R7 is CONHOC ^ alkylOH, or Cu alkyl is optionally substituted by hydroxyl, or R7 is phenyl or 5- or 6-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N and O. 10 The compound according to any one of items 1 to 3 of the scope of the patent application, wherein the group A, plus the phenyl group attached thereto, forms a bicyclic group of the formula (A) or (B): Among them, R4 and R5 are as defined in item 1 of the scope of patent application. 1 1. A compound which is 8- (1′-benzimidazol-2-ylsulfanyl) -4 (1 ′)-quinone, 8-[(5-chloro-1H-benzimidazole-2- Group) sulfanyl] -4 (1H) -quinone, 2- (4-keto-1,4-dihydro-pyridin-8-ylsulfanyl) -1 fluorene-benzimidazole-4 -Methyl double acid, 8-[(5 -Chloro-1 并 -benzimidazole-2 -yl) sulfanyl] -5 · nitro-fluorene (1Η) -p-quinolone 5-amino-8- [(5 -Chloro-1H-benzimidazol-2-yl) sulfanyl] -4- (1Η) -Acetone 8-[(5-Chloro-1H-benzimidazol-2-yl) sulfan Yl] -5-{[((2R) -pyrrolidin-4-200410687 Methylmethyl] amino} -4 (1 fluorene) -quinone 8-[(5-chloro-1fluorene-benzimidazol-2-yl) sulfanyl] -5-[(4-piperidinylmethyl (Amino) amino] -4 (1 Η) -quinolones 5-chloro-2-[(4-keto-1,4-dihydroquinolin-8-yl) thio] -1Η-benzimidazole- 4-nitrile, 5-chloro-2-[(4-keto-1,4-dihydroquinolin-8 · yl) sulfur] -1 hydrazone-benzimidazole • 4-carboxylic acid methyl ester N- {5 -Chloro- 2-[(4-keto-1,4-dihydroquinolin-8-yl) sulfur] -1'-benzimidamine-4 -yl} benzamide, Ν-{5 -chloro- 2-[(4-keto-1,4-dihydroquinolin-8-yl) sulfur] · 1 hydrazone -benzimidone-4 -kib 2 -furanamide, 4-[(5 -chloro _ 1 pyrene-benzimidazole-2 -yl) sulfur] -1,3-dihydro-2 pyrene-benzimidazole-2, 7-[(5-chloro-1pyrene-benzimidazole-2- Group) thio] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxylic acid, or 7-[(5-chloro-4- (methoxycarbonyl) -1fluorene-benzo Imidazol-2-yl) sulfur] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxylic acid is in the form of a base, salt, solvate or solvate of its salt. 1 2. A compound which is 7-[(5-chloro- 4-[(2-hydroxyethoxy) carbonyl] -1Η-benzimidazole · 2-yl) thio] -2 -keto-2 , 3-dihydro-1 hydrazone-benzimidazole-5 -carboxylic acid, 7-[(5-chloro-1hydrazone-benzimidazol-2-yl) sulfur] -2 -keto-2,3 -dihydro -1Η-benzimidazole-5 -carboxylic acid methyl ester, 7-[(5-chloro-1 Η-benzimidazole-2 -yl) sulfur] -2 -keto-2,3-dihydro-1 Η - 200410687 benzimidazole-5 ^ leptate ethyl ester, 7 · [(5-chloro-1H-benzimidazol-2-yl) sulfur] -2-one- 2,3-dihydro-1H-benzimidazole -5 -carboxylic acid 2 -Naufolin-4 -ylethyl ester, 7-[(5 -Rat-6-gas-1H -Feng and Weijun-2 -yl) sulfur] -2 -Ethyl-2 , 3 -dihydro_ 1 Η -benzimidazole-5 -carboxylic acid, 7-[(5-methoxy-1 甲 -benzimidazol-2-yl) sulfur] -2 -keto-2,3- Dihydro-1 fluorene-benzimidazole-5-carboxylic acid, 7-[(5-bromo-1 fluorene-benzimidazole-2 -yl) sulfur] -2 -keto-2,3-dihydro-1 Hydrazone-benzimidazole-5 -carboxylic acid, 7-[(4-bromo-6 · fluoro-1fluorene-benzimidazole-2 -yl) sulfur] -2 -keto-2,3 -dihydro-1fluorene- Benzimidazole-5-carboxylic acid, 7-[(5-bromo · 1Η-benzimidazol-2-yl) thio] -2-one- 2,3-dihydro-1 氢 -benzimidazole-5 -Chinoic acid, 7-[(5-chloro-1fluorenyl-benzimidazole-2 · yl) sulfur] -N- [2_ (4-morpholine-4-ylethyl) -2 -keto-2, 3 -dihydro-1 hydrazone-benzimidazole-5 -carboxamide, 7-[(5-chloro-1fluorene-benzimidazol-2-yl) sulfur] -N- [3-dimethylamino] ethyl Yl] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxamide, 4-[(5-chloro-1fluorene-benzimidazole-2-yl) sulfur] -6- [(4-methylpipen-1-yl) Carbonyl-1,3-dihydro-2'-benzimidazol-2-one, 7-[(5-chloro-1'-benzimidazol-2-yl) sulfur] -N-methyl-2 · keto -2,3 -dihydro-1 hydrazone -benzimidazole-5 _carboxamidine, 7-[(5 · chloro-1Η-benzimidazol-2-yl) sulfur] -N- (2-hydroxyethyl ) -2-keto-2,3-dihydro_ 1 fluorene-benzimidazole-5 -carboxamide, 4-[(5-chloro-1 fluorene -benzimidazole-2 -yl) sulfur] -6 -(Pigen-1 carbonyl) 200410687 -1,3-dihydro-2 hydrazone-benzimidazol-2-one dihydrochloride, 7-[(5 · chloro-1hydrazone-benzimidazol-2-yl) sulfur] _2-keto-2, 3-dihydro_1Η-benzimidazole-5-carboxamidine, 7 · [(5 -qi-1Η-capsulose-2 -yl) sulfur] -N- [2- (2-up to Ethoxy) ethyl] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxamide, 4-[(5-Chloro-1H-benzimidazol-2-yl) sulfur] -6-{[4- (2-hydroxyethyl) piperin-1-yl] carbonylb 1,3-dihydro- 2H-benzimidazol-2-one, 7-[(5-chloro-1H-benzimidazole'2-yl) thio] -2-one, radical- > ^ 4-piperin-4-yl-2 , 3 -dihydro-1 fluorene-benzimidazole-5 -carboxamide dihydrochloride, N- (3-aminopropyl) -7-[(5-chloro-1fluorene-benzimidazole-2_ (Yl) thio] -2-keto-2,3-dihydro-1fluorene-benzimidazole-5-carboxamide dihydrochloride, 7-[(5-chloro-111-benzimidazol-2-yl )] Thio-2-keto-1 ^-[3- (2-ketopyrrolidin-1-yl) propyl] -2,3-dihydro-1fluorene-benzimidazole-5-carboxamide, or 4-[(5-Chloro-l-benzimidazol-2-yl) sulfur] -6- (hydroxymethyl) -1,3-dihydro-2 hydrazone-benzimidazole-2 -one, 'dihydro -2 fluorene-benzimidazol-2-one, in the form of a solvate of a base, a salt, a solvate or a salt thereof. 1 3. — Compound of formula (I) R4 200410687 Among them: · R1 is hydrogen, C02R7, NHCOR7, or halogen; R2 is hydrogen or halogen; R3 is hydrogen or halogen; R4 is hydrogen, NH24 N02; R5 is hydrogen; R7 is Cu alkyl, if required, 1, 2 Or 3 substituents independently selected from a hydroxyl group; A is a 5-membered aromatic ring containing one or more heteroatoms independently selected from N and 0; and the ring may be one or more independently selected from an alkyl group as required, S02CL6 alkyl, SOCbs alkyl, and CHO substituents are substituted, showing the test, salt, solvate or salt solvate type. 14. The compound according to item 13 of the scope of the patent application, wherein the A group plus the phenyl group attached thereto forms a tricyclic group of the formula (C): Among them, R4 and R5 are as defined in item 13 of the scope of patent application, and R2G is soch3, S02CH3, CH3, C02H or CHO. 1 5. — Compounds, which are: 7-[(5 -Chloro-1 fluorene -benzimidazole-2 -yl) sulfur] -3-(methylsulfonyl) 200410687 Patent Application Fact Sheet-1H- , Indole-4-linked, 5-chloro-2-{[3- (methylsulfonyl) -1Η-fluoren-7-yl] sulfur} -1Η-benzimidone-4 -acid methyl acetate , 5-chloro- 2-{[3-methyl-4-nitro-1H-raldol-7-yl] thio} _1H-benzimidazoline, 7-[(5-chloro-1 fluorene-benzene Benzimidazole-2-yl) sulfur] -3 -methyl-1 fluorene-, indole 4-amine, 5-chloro-2-{[3-(methylsulfinamilide) -4 -nitro-1 Fluorene-Wind-7-yl] sulfur}-1 fluorene-benzimidazole, _ 7-[(5-chloro-1 fluorene-benzimidazole-2 -yl) sulfur] -3-(methylsulfinylhydrazone Group) -1 fluorene-indole-4 -amine, 4-amino-7-[(5-chloro-1fluorene-benzimidazol-2-yl) sulfur] -1 fluorene-fluorene-3-aldehyde, or 7 -[(5 -Chloro-1Η-benzimidazole-2 -yl) sulfur] -3-(methylsulfonamido) _ 1 Η-oxindole, which is a base, salt, solvate or solvate of its salt Pattern. 16. The compound according to item 1 of the scope of patent application, wherein the salt is a pharmaceutically acceptable salt. 17. A method for preparing a compound as defined in item 1 or 13 of the scope of the patent application, which method comprises: (a) a compound of formula (II): 200410687 Where A, R4 and R5 are as defined in formula (I), and L is a leaving group, or Where A, R4 and R5 are as defined in formula (I), and compounds of formula (V) (V) R: R -10- 0 0200410687 Wherein R1, R2 and R3 are as defined in Formula (I), and Lf is a leaving group. 18. A method for preparing a compound according to item 1, in the scope of patent application, which method comprises converting a compound of formula (VI), wherein R5 is a carboxyl group and R1, R2, R3 and R4 are as defined in item 1 of the scope of patent application , Into a compound of formula (la), wherein R1, R2, R3, R4 and R5 are as defined in item 1 of the scope of patent application, 19. A compound of formula (I) as defined in item 1 or 16 of the scope of the patent application, which is for use in therapy. 2 0. The use of a compound of formula (I), a salt, a solvate or a salt solvate thereof, as defined in item 1 or 16 of the scope of the patent application, for the preparation of a medicament for treating JNK-mediated conditions. 2 1. A compound of formula (I) as defined in item 1 or 16 of the scope of the patent application, the salt, solvate or salt solvate of which is used for the preparation of therapeutic agents, such diseases include: Hemel disease, Parkinson's disease, ALS, epilepsy 'and seizures, Huntington's disease, traumatic brain injury or hemorrhagic stroke. 22. For the treatment of Alzheimer's disease according to item 21 of the scope of patent application -11-200410687 Of its purpose. '. 2 3. — A pharmaceutical composition comprising a' therapeutically effective amount 'of a compound as defined in item 1 or 16 of the scope of the patent application, and a pharmaceutically acceptable excipient , Diluent and / or inert carrier are mixed. ♦ 24. The pharmaceutical composition according to item 23 of the scope of patent application, which is used to treat the condition of JNK mediation. 25. A pharmaceutical composition according to item 23 of the scope of patent application, which is used to treat Alzheimer's disease, Parkinson's disease, ALS, epilepsy and seizures, Huntington's disease, traumatic brain injury or hemorrhagic Stroke. 2 6. The medical composition according to item 23 of the scope of patent application, which is used to treat Alzheimer's disease. 27. — Compounds of Formula (VI) Wherein: R1 is hydrogen, C02R7, NHCOR7, CN or halogen; R2 is hydrogen, halogen, OCu alkyl, or 5 · or 6-membered heterocyclic ring, which contains 1, 2 or 3 independently selected from N, O and S Hetero atom; and R3 is hydrogen or halogen; R6 is Ci_6 alkyl, which is 1, 2 or 3 independently selected from hydroxyl, OCi-6 -12-200410687 Alkyl, substituted by 0 (^-6 alkylOH and NR12R13 substituents; R7 is CONHOChs alkyl OH, or Cb6 alkyl as required 1, 2, 3 or 4 independently selected from hydroxyl, OCu alkyl and NR12R13 is substituted by a substituent, or R7 is a phenyl group or a 5- or 6-membered heterocyclic ring, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, 0 and S, as its salt, solvate Or salt solvate type. 28. —The use of a compound of formula (VI) as an intermediate to prepare a compound according to item 1 of the scope of patent application. -13- 200410687 Lu, (a), the designated representative of this case is: Figure _ (b), the symbolic representation of the components in this table is simply explained: 罾 柒 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 200410687 No. 91136653 Patent Application Specification Replacement Page (July 1992) Inventor 2 Name: (Chinese) Sain Emperor J: English) SIMON TEAGUE__ —_ Address of Residence: (Chinese) Benai, Roberloef, UK _) BAKEWELL ROAD, LOUGHBOROUGH. LEICS. LE11 5RH, UNITED KINGDOM _ Nationality : Text) United Kingdom __ (English) UNITED KINGDOM_ Inventor 3 Name: ^ ± Text) Adarzi ____ 丄 English) YAFENGXUE___ Address of Residence: (Chinese) S-43183_ θ in Monjer, Sweden) S-431 83 M0LNDAL · SWEDRN_; _ Nationality: ^ Wen) China _ (English) PEOPLE'S REPUBLIC OF CHINA Inventor 4 Name: Ct Wen) Ministry of Tamari Mary __ -LMlK) BRITT-MAT? TF SWAHN___ Residence; Address : (Chinese) Panpanzhai Detelai SE-15185__ 丄 English) SE-151 85 S0DERTALJE · SWEDEN_ Nationality: Wen) Sweden __ (benzene) SWEDEN '_